Treatment of insulin resistance with growth hormone secretagogues

ABSTRACT

This invention is directed to methods of treating insulin resistance in a mammal which comprise administering an effective amount of a compound of formula I,  
                 
 
     where the variables are defined in the specification, or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers, or the pharmaceutically acceptable salts and prodrugs thereof to said mammal. The compounds of formula I are growth hormone secretagogues and as such are useful for increasing the level of endogenous growth hormone. In another aspect this invention provides certain intermediates which are useful in the synthesis of the foregoing compounds and certain processes useful for the synthesis of said intermediates and the compounds of formula I. This invention is further directed to methods comprising administering to a human or other animal a combination of a functional somatostatin antagonist such as an alpha-2 adrenergic agonist and a compound of formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a divisional application of U.S. Ser. No. 09/380,186,filed Aug. 26, 1999, now allowed, which was the National Stage ofInternational Application No. PCT/IB98/00876, filed Jun. 5, 1998, whichwas published in English under PCT Article 21(2) on Dec. 30, 1998.

BACKGROUND OF THE INVENTION

[0002] Growth hormone (GH), which is secreted from the pituitary gland,stimulates growth of all tissues of the body that are capable ofgrowing. In addition, growth hormone is known to have the followingbasic effects on the metabolic processes of the body:

[0003] 1. Increased rate of protein synthesis in substantially all cellsof the body;

[0004] 2. Decreased rate of carbohydrate utilization in cells of thebody; and

[0005] 3. Increased mobilization of free fatty acids and use of fattyacids for energy.

[0006] Deficiency in growth hormone results in a variety of medicaldisorders. In children, it causes dwarfism. In adults, the consequencesof acquired GH deficiency include profound reduction in lean body massand concomitant increase in total body fat, particularly in the truncalregion. Decreased skeletal and cardiac muscle mass and muscle strengthlead to a significant reduction in exercise capacity. Bone density isalso reduced. Administration of exogenous growth hormone has been shownto reverse many of the metabolic changes. Additional benefits of therapyhave included reduction in LDL cholesterol and improved psychologicalwell-being.

[0007] In cases where increased levels of growth hormone were desired,the problem was generally solved by providing exogenous growth hormoneor by administering an agent which stimulated growth hormone productionand/or release. In either case the peptidyl nature of the compoundnecessitated that it be administered by injection. Initially the sourceof growth hormone was the extraction of the pituitary glands ofcadavers. This resulted in an expensive product, and carried with it therisk that a disease associated with the source of the pituitary glandcould be transmitted to the recipient of the growth hormone (e.g.,Jacob-Creutzfeld disease). Recently, recombinant growth hormone hasbecome available which, while no longer carrying any risk of diseasetransmission, is still a very expensive product which must be given byinjection or by a nasal spray.

[0008] Most GH deficiencies are caused by defects in GH release, notprimary defects in pituitary synthesis of GH. Therefore, an alternativestrategy for normalizing serum GH levels is by stimulating its releasefrom somatotrophs. Increasing GH secretion can be achieved bystimulating or inhibiting various neurotransmitter systems in the brainand hypothalamus. As a result, the development of synthetic growthhormone-releasing agents to stimulate pituitary GH secretion are beingpursued, and may have several advantages over expensive and inconvenientGH replacement therapy. By acting along physiologic regulatory pathways,the most desirable agents would stimulate pulsatile GH secretion, andexcessive levels of GH that have been associated with the undesirableside effects of exogenous GH administration would be avoided by virtueof intact negative feedback loops.

[0009] Physiologic and pharmacologic stimulators of GH secretion includearginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin,and insulin induced hypoglycemia, as well as activities such as sleepand exercise, indirectly cause growth hormone to be released from thepituitary by acting in some fashion on the hypothalamus perhaps eitherto decrease somatostatin secretion or to increase the secretion of theknown secretagogue growth hormone releasing factor (GHRF) or an unknownendogenous growth hormone-releasing hormone or all of these.

[0010] Other compounds have been developed which stimulate the releaseof endogenous growth hormone such as analogous peptidyl compoundsrelated to GRF or the peptides of U.S. Pat. No. 4,411,890. Thesepeptides, while considerably smaller than growth hormones are stillsusceptible to various proteases. As with most peptides, their potentialfor oral bioavailability is low. WO 94/13696 refers to certainspiropiperidines and homologues which promote release of growth hormone.

[0011] The compounds of WO 94/11012 and WO 94/13696 are reported to beuseful in the treatment of osteoporosis in combination with parathyroidhormone or a bisphosphonate.

[0012] In one aspect, this invention relates to a method of treatinginsulin resistant conditions such as Non-Insulin Dependent DiabetesMellitus (NIDDM) and reduced glycemic control associated with obesityand aging in a mammal in need thereof which comprises administering tosaid mammal an effective amount of a compound of the formula I, definedbelow, or a pharmaceutically acceptable salt thereof.

[0013] This invention is directed to the use of growth hormonesecretagogues specifically growth hormone releasing peptides (GHRP) orGHRP mimetics of formula I, defined below, to improve glycemic control.Agents that increase growth hormone (GH) levels would not be expected tohave this effect since it is widely recognized that GH is diabetogenicin animals and in humans. In acromegalics, glucose utilization andsuppression of hepatic glucose production are impaired (see Hansen, I.,et al., Am J Physiol, 250:E269 (1986)). In this disease of GH excess,impaired glucose handling and hyperinsulinemia have been reversed bypituitary surgery or chemotherapy which reduced GH levels (see Levin S.R., et al., Am J Med, 57:526 (1974), Feek, C. M., et al., J ClinEndocrinol 22:532 (1981)). Furthermore, administration of GH to oldersubjects caused hyperglycemia, glucose intolerance and hyperinsulinemiain numerous studies (see Aloia, J. F., et al., J Clin Endocrinol Metab,43:992 (1976); Binnerts et al., J Clin Endocrinol Metab, 67:1312 (1988);Marcus, R., et al., J Clin Endocrinol Metab, 70:519 (1990)). Therefore,GH therapy is contra-indicated for individuals with diabetes or those atrisk for diabetes.

[0014] Obesity is a major risk factor for diabetes, and a large fractionof NIDDM patients are obese. Both conditions are characterized byelevated circulating insulin levels and suppressed GH levels. GHtreatment of GH-deficient adults (Jorgensen, J. O. L., et al., Lancet1:1221 (1989)), obese women (Richelsen, B., et al., Am J Physiol,266:E211 (1994)) and elderly men (Rudman, D., et al, Horm Res 36 (Suppl1):73 (1991)) has been shown to produce increases in lean body, hepaticand muscle mass while decreasing fat mass. Thus, GH therapy for obesitywould seem attractive except for the diabetogenic effects of GH.

[0015] An alternative to exogenous GH administration is therapy thatstimulates endogenous GH secretion. It has been shown that a substantialpituitary reserve of GH is present in pituitary-intact GH-deficientpatients and the elderly so that decreased serum GH levels are due tohyposecretion.

[0016] Hyposecretion of GH in several clinical settings (obesity, aging,glucocorticoid suppression) is relatively resistant to stimulation byGHRH (Gertz, B. J., et al., J Clin Endocrinol Metab, 79:745 (1994);Arvat, E., et al., J Clin Endocrinol Metab, 79:1440 (1994); Maccario,M., et al., Metabolism, 44:134 (1995)). In contrast, administration of aGHRP or combined administration of GHRH and a GHRP in these patients canelicit a robust GH response (Aloi, J. A., et al., J Clin EndocrinolMetab, 79:943; (1994)). Single dose studies of GHRPs have demonstratedthe absence of an acute effect on circulating insulin or glucose levels.Insulin and glucose have generally not been monitored in chronic studiesexcept to document the absence of unfavorable changes (Jacks, T., etal., J Endocrinol. 143:399 (1993)).

[0017] Prior to the present invention, the use of GHRPs or GHRP mimeticsto improve glycemic control has not specifically been explored. Themethod of treating insulin resistance in a mammal comprising theadministration of a compound of formula I is practiced preferentially inpatients who have a functional hypothalamic-pituitary axis capable of GHsecretory responses to GHRPs and who are diabetics (Type I or Type II),or are insulin resistant, or who show impaired glucose tolerance.

[0018] In another aspect, this invention is directed to methods for thetreatment or prevention of congestive heart failure, obesity and frailtyassociated with aging, in a mammal in need thereof, which comprisesadministering to said mammal simultaneously, sequentially in any orderor as a combination a functional somatostatin antagonist such as analpha-2 adrenergic agonist, for example clonidine, xylazine ormedetomidine, and a compound of formula I, defined below. In anotheraspect, this invention provides methods for accelerating bone fracturerepair and wound healing, attenuating protein catabolic response after amajor operation, and reducing cachexia and protein loss due to chronicillness in a mammal in need thereof, which comprises administering tosaid mammal simultaneously, sequentially in any order or as acombination an alpha-2 adrenergic agonist, such as clonidine, xylazineor medetomidine and a compound of formula I, defined below. Clonidine,which is disclosed in U.S. Pat. No. 3,202,660 the disclosure of which ishereby incorporated by reference, xylazine, which is disclosed in U.S.Pat. No. 3,235,550 the disclosure of which is hereby incorporated byreference and medetomidine, which is disclosed in U.S. Pat. No.4,544,664 the disclosure of which is hereby incorporated by reference.It has been shown that alpha-2 adrenergic agonists cause release ofendogenous growth hormone in human and canine subjects (Cella et al.,Life Sciences (1984), 34:447-454; Hampshire J, Altszuler N. AmericanJournal of Veterinary Research (1981), 42:6, 1073-1076; Valcavi et al.,Clinical Endocrinology (1988), 29:309-316; Morrison et al., AmericanJournal of Veterinary Research (1990), 51:1, 65-70;), and that theco-administration of an alpha-2 adrenergic agonist with growthhormone-releasing factor restores defective growth hormone secretion inaged dogs (Arce et al., Brain Research (1990), 537:359-362; Cella et.al., Neuroendocrinology (1993), 57:432-438).

[0019] In yet another aspect, this invention provides a process for thesynthesis of a compound of the formula Z

[0020] where the process is described below.

[0021] Further, this invention is directed to processes for preparingcertain intermediates, shown below, which are useful in the synthesis ofthe compound of formula Z.

[0022] The compounds of formula I utilized in the present invention andthe compound of formula Z are disclosed and claimed in co-pending PCTApplication Number PCT/IB 96/01353 filed Dec. 4, 1996, which is assignedto the assignee hereof, wherein said compounds are disclosed as havingactivity as growth hormone secretagogues and which increase the level ofendogenous growth hormone.

SUMMARY OF THE INVENTION

[0023] The compounds utilized in methods of this invention have theformula I,

[0024] or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers, or the pharmaceutically acceptable salts and prodrugsthereof,

[0025] wherein

[0026] e is 0 or 1;

[0027] n and w are each independently 0, 1 or 2;

[0028] provided that w and n cannot both be 0 at the same time;

[0029] Y is oxygen or sulfur;

[0030] R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N (X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹,—(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)SO₂N (X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X ⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

[0031] where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro;

[0032] Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—,—C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

[0033] q is 0, 1, 2, 3 or 4;

[0034] t is 0,1,2 or 3;

[0035] said (CH₂)_(q) group and (CH₂)_(t) group may each be optionallysubstituted with hydroxyl, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro, or 1 or 2 (C₁-C₄)alkyl;

[0036] R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹;

[0037] where the alkyl groups and the cycloalkyl groups in thedefinition of R² are optionally substituted with hydroxyl, —C(O)OX⁶,—C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶),CF₃, CN or 1, 2 or 3 halogen;

[0038] R³ is A¹, (C₁-C₁₀)alkyl, —(C₁-C₆)alkyl-A¹,—(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl;

[0039] where the alkyl groups in the definition of R³ are optionallysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5halogens, or 1, 2 or 3 OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—,—OC(O)—, —C(O)O—, —CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—;

[0040] R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is takentogether with R³ and the carbon atom to which they are attached and form(C₅-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl, a partially saturated or fullysaturated 4- to 8-membered ring having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or isa bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, fused to a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

[0041] X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴and the nitrogen atom to which X⁴ is attached and the carbon atom towhich R⁴ is attached and form a five to seven membered ring;

[0042] R⁶ is a bond or is

[0043] where a and b are independently 0, 1, 2 or 3;

[0044] X⁵ and X^(5a) are each independently selected from the groupconsisting of hydrogen, trifluoromethyl, A¹ and optionally substituted(C₁-C₆)alkyl;

[0045] the optionally substituted (C₁-C₆)alkyl in the definition of X⁵and X^(5a) is optionally substituted with a substituent selected fromthe group consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

[0046] or the carbon bearing X⁵ or X^(5a) forms one or two alkylenebridges with the nitrogen atom bearing R⁷ and R⁸ wherein each alkylenebridge contains 1 to 5 carbon atoms, provided that when one alkylenebridge is formed then X⁵ or X^(5a) but not both may be on the carbonatom and R⁷ or R⁸ but not both may be on the nitrogen atom and furtherprovided that when two alkylene bridges are formed then X⁵ and X^(5a)cannot be on the carbon atom and R⁷ and R⁸ cannot be on the nitrogenatom;

[0047] or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen;

[0048] or X⁵ is taken together with X⁵a and the carbon atom to whichthey are attached and form a bicyclic ring system consisting of apartially saturated or fully saturated 5- or 6-membered ring, optionallyhaving 1 or 2 heteroatoms independently slected from the groupconsisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen;

[0049] Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O;

[0050] R⁷ and R⁸ are independently hydrogen or optionally substituted(C₁-C₆)alkyl;

[0051] where the optionally substituted (C₁-C₆)alkyl in the definitionof R⁷ and R⁸ is optionally independently substituted with A¹,—C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3hydroxy, 1 to 3-O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or

[0052] R⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—;

[0053] where L is C(X²)(X²), S(O)_(m) or N(X²);

[0054] A¹ for each occurrence is independently (C₅-C₇)cycloalkenyl,phenyl or a partially saturated, fully saturated or fully unsaturated 4-to 8-membered ring optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, abicyclic ring system consisting of a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

[0055] A¹ for each occurrence is independently optionally substituted,in one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,

[0056] (C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², NX⁶SO₂X¹²,NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², NX⁶C(O)X¹², imidazolyl, thiazolyl andtetrazolyl, provided that if A¹ is optionally substituted withmethylenedioxy then it can only be substituted with one methylenedioxy;

[0057] where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

[0058] the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3hydroxy, 1 to 3 (C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy;

[0059] X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl,furyl or thienyl, provided that when X¹² is not hydrogen, X¹² isoptionally substituted with one to three substituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

[0060] or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)^(r)—;

[0061] where L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

[0062] r for each occurrence is independently 1, 2 or 3;

[0063] X² for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl,where the optionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³;

[0064] X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0065] X⁶ is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated-cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently substituted by 1 or 2(C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester, or1H-tetrazol-5-yl; or

[0066] when there are two X⁶ groups on one atom and both X⁶ areindependently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9- membered ring optionally having oxygen,sulfur or NX⁷;

[0067] X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted withhydroxyl; and

[0068] m for each occurrence is independently 0, 1 or 2;

[0069] with the proviso that:

[0070] X⁶ and X¹² cannot be hydrogen when it is attached to C(O) or SO₂in the form C(O)X⁶(O)(O)X¹², SO₂X⁶ or SO₂X¹²; and

[0071] when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3.

[0072] In one aspect, this invention provides a method for treatinginsulin resistance in a mammal which comprises administering to saidmammal an effective amount of a compound of formula I, as defined above,or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers, or the pharmaceutically acceptable salts and prodrugsthereof.

[0073] A preferred method of the foregoing method is where the conditionassociated with insulin resistance is type I diabetes, type II diabetes,hyperglycemia, impaired glucose tolerance or an insulin resistantsyndrome or state.

[0074] Another preferred method of the foregoing method is where thecondition associated with insulin resistance is associated with obesityor old age.

[0075] A preferred method of the foregoing method is where said compoundof formula I is of the following formula

[0076] or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers, or the pharmaceutically acceptable salts and prodrugsthereof where

[0077] R¹ is —CH₂-phenyl, R² is methyl and R³ is —(CH₂)₃-phenyl;

[0078] R¹ is —CH₂-phenyl, R² is methyl and R³ is 3-indolyl-CH₂—;

[0079] R¹ is —CH₂-phenyl, R² is ethyl and R³is 3-indolyl-CH₂—;

[0080] R¹ is —CH₂-4-fluoro-phenyl, R² is methyl and R³ is3-indolyl-CH₂—;

[0081] R¹ is —CH₂-phenyl, R² is methyl and R³is —CH₂—O—CH₂-phenyl;

[0082] R¹ is —CH₂-phenyl, R² is ethyl and R³ is —CH₂—O—CH₂-phenyl;

[0083] R¹ is —CH₂-phenyl, R² is —CH₂CF₃ and R³ is —CH₂—O—CH₂-phenyl;

[0084] R¹ is —CH₂-4-fluoro-phenyl , R² is methyl and is—CH₂—O—CH₂-phenyl;

[0085] R¹ is —CH₂-phenyl, R² is t-butyl and R³ is —CH₂—O—CH₂-phenyl; or

[0086] R¹ is —CH₂-phenyl, R² is methyl and R³ is—CH₂—O—CH₂-3,4-di-fluoro-phenyl.

[0087] Another preferred method of the foregoing method is where saidcompound of formula I is of the formula

[0088] or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers, or the pharmaceutically acceptable salts and prodrugsthereof where

[0089] R² is methyl; A¹ is 2-pyridyl; and R³ is —CH₂—O—CH₂-phenyl;

[0090] R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-3-chloro-phenyl;

[0091] R² is CH₂CF₃; A¹ is 2-pyridyl; and R³is—CH₂—O—CH₂-4-chloro-phenyl;

[0092] R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-2,4-di-chloro-phenyl;

[0093] R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-3-chloro-thiophene or

[0094] R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-2,4-di-fluoro-phenyl.

[0095] Yet another preferred method of the foregoing method is wheresaid compound of formula I or the stereoisomeric mixtures,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomers or the pharmaceuticallyacceptable salts and prodrugs thereof is the 3a(R,S), 1(R)diastereomeric mixture, the 3a(R), 1(R) diastereomer or the 3a(S), 1(R)diastereomer of a compound selected from the group consisting of

[0096]2-amino-N-[1-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-butyl]-isobutyramide,

[0097]2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl)-isobutyramide,

[0098]2-amino-N-[2-(3a-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide,

[0099]2-amino-N-[2-[3a-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide,

[0100]2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,

[0101]2-amino-N-{2-(3a-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-benzyloxymethyl-2-oxo-ethyl}-isobutyramide,

[0102]2-amino-N-{1-benzyloxymethyl-2-[3a-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramide,

[0103] 2-amino-N-[2-(3a-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-isobutyramideand

[0104]2-amino-N-[2-(3a-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-isobutyramide.

[0105] A preferred method of the immediately foregoing method is wheresaid compound of formula I is2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylp9-isobutyramide L-tartaric acid salt.

[0106] Still anothe preferred method of the foregoing method is a methodwhere said compound of formula I or the stereoisomeruic moixtures,disateromerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomers or the pharmaceuticallyacceptable salts and prodrugs thereof is the 3a -(R,S),1-(R)diastereomeric mixture, the 3a-(R), 1-(R) enantiomer or 3a-(S), 1-(R)enantiomer of a compound selected from the group consisting of

[0107]2-amino-N-[1-benzyloxymethyl-2-(2-methyl-3-oxo-3a-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide;

[0108]2-amino-N-{1-(3-chloro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide;

[0109]2-amino-N-{1-(4-chloro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide;

[0110]2-amino-N-{1-(2,4-dichloro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide;

[0111]2-amino-N-{1-(1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyrid-2-ylmethy;-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide.

[0112] Even still another preferred method of the foregoing methodadditionally comprises administering to a mammal in need thereof agrowth hormone releasing hormone or a functional analog thereof, whichare prepared by methods known in the art and some examples of which aredescribed in European Patent Publication No. EP 511 003.

[0113] In another aspect, this invention provides pharmaceuticalcompositions useful for treating insulin resistance in a mammal whichcomprises a pharmaceutically acceptable carrier and an effective amountof a compound of formula I, as shown above, or the stereoisomericmixtures, diastereomerically enriched, diastereomerically pure,enantiom,ericlaly enriched or enantiomerically pure isomers, or thepharmaceutically acceptable salts and prodrugs thereof.

[0114] In still another aspect, this invention provides methods forincreasing levels of endogenous growth hormone, which comprisesadministering to a human or other animal in need thereof effectiveamounts of a functional somatostatin antagonist and a compound offormula I, as shown above, or the stereoisomeric mixtures,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomers, or the pharmaceuticallyacceptable salts and prodrugs thereof.

[0115] In yet another aspect, this invention provides methods oftreating or preventing congestive heart failure, obesity or frailtyassociated with aging, which comprises administering to a mammal in needthereof effective amounts of a functional somatostatin antagonist and acompound of formula I, as shown above, or the stereoisomeric mixtures,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomers, or the pharmaceuticallyacceptable salts and prodrugs thereof. Preferred of the immediatelyforegoing method is where said functional somatostatin antagonist is analpha-2 adrenergic agonist. Preferred of the immediately foregoingmethod is where said alpha-2 adrenergic agonist is selected from thegroup consisting of clonidine, xylazine and medetomidine. Preferred ofthe immediately foregoing method is where said compound of formula I is2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideL-tartaric acid salt.

[0116] This invention is also directed to pharmaceutical compositionswhich comprise a pharmaceutically acceptable carrier, an amount of analpha-2 adrenergic agonist and an amount of a compound of formula I, asdefined above, or the stereoisomeric mixtures, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomers, or the pharmaceutically acceptable saltsand prodrugs thereof.

[0117] This invention is further directed to methods of treating insulinresistance in a mammal which comprise administering to a mammal in needthereof an effective amount of a growth hormone releasing peptide or agrowth hormone releasing peptide mimetic or a pharmaceuticallyacceptable salt thereof.

[0118] In one aspect, this invention is directed to the processesdescribed below, where the “*” indicates stereochemical centers.

[0119] A process for the preparation of the compound of formula k,

[0120] which comprises reacting the compound of formula g,

[0121] with the compound of formula j,

[0122] where Prt is an amine protecting group, in the presence of anorganic base, a peptide coupling reagent, and a reaction inert solventat a temperature between about −78° C. to about −20° C. to yield thecompound of formula k.

[0123] Preferred of the foregoing process is where the peptide couplingreagent is 1-propane phosphonic acid cyclic anhydride and the compoundof formula g has the R-configuration, the compound of formula j has theR-configuration and the compound of formula k has the 3a-(R), 1-(R)configuration.

[0124] A process for the preparation of the compound of formula Z,

[0125] which comprises reacting the compound of formula g,

[0126] with the compound of formula j,

[0127] in the presence of an organic base, a peptide coupling reagent,and a reaction inert solvent at a temperature between about −78° C. toabout −20° C. to yield the compound of formula k,

[0128] deprotecting the compound of formula k to yield the compound offormula I,

[0129] reacting the compound of formula I with L-tartaric acid in analcoholic solvent to yield the compound of formula Z.

[0130] Preferred of the immediately foregoing process is where thepeptide coupling reagent is 1-propane phosphonic acid cyclic anhydrideand the compound of formula g has the R-configuration, the compound offormula j has the R-configuration and each of the compounds of formulak, I and Z has the 3a-(R), 1-(R) configuration.

[0131] A process for the preparation of the compound of formula g,

[0132] which comprises reacting the compound of formula f,

[0133] with a base in an inert solvent at a temperature of about −50 to−10° C. wherein the chirality of the benzyl group is maintained, toyield the compound of formula g.

[0134] A process for the preparation of the compound of formula c,

[0135] which comprises reacting the compound of formula b,

[0136] where Prt is an amine protecting group, with an inorganic ororganic base and benzyl bromide in a reaction inert solvent to yield thecompound of formula c.

[0137] A process for the preparation of the compound of formula f,

[0138] which comprises reacting the compound of formula e,

[0139] with L-tartaric acid in a reaction inert organic solvent.

[0140] This invention also provides the R,S-enantiomeric mixture, theR-enantiomer or the S-enantiomer of the compound of formula

[0141] where Prt is hydrogen or an amine protecting group.

DETAILED DESCRIPTION OF THE INVENTION

[0142] In general the compounds of formula I or the stereoisomericmixtures, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomers, or thepharmaceutically acceptable salts and prodrugs thereof, utilized inmethods of the instant invention can be made by processes which includeprocesses known in the chemical arts.

[0143] In the above structural formulae and throughout the instantapplication, the following terms have the indicated meanings unlessexpressly stated otherwise.

[0144] The alkyl groups are intended to include those alkyl groups ofthe designated length in either a straight or branched configurationwhich may optionally contain double or triple bonds. Exemplary of suchalkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl,propenyl, butadienyl, hexenyl and the like.

[0145] When the definition C₀-alkyl occurs in the definition, it means asingle covalent bond.

[0146] The alkoxy groups specified above are intended to include thosealkoxy groups of the designated length in either a straight or branchedconfiguration which may optionally contain double or triple bonds.Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy,hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxyand the like.

[0147] The term “halogen” or “halo” is intended to include the halogenatoms fluorine, chlorine, bromine and iodine.

[0148] The term “halogenated alkyl” is intended to include an alkylgroup as defined hereinabove substituted by one or more halogen atoms asdefined hereinabove.

[0149] The term “halogenated cycloalkyl” is intended to include acycloalkyl group substituted by one or more halogen atoms as definedhereinabove.

[0150] The term “aryl” is intended to include phenyl and naphthyl andaromatic 5- and 6-membered rings with 1 to 4 heteroatoms or fused 5- or6-membered bicyclic rings with 1 to 4 heteroatoms of nitrogen, sulfur oroxygen. Examples of such heterocyclic aromatic rings are pyridine,thiophene (also known as thienyl), furan, benzothiophene, tetrazole,indole, N-methylindole, dihydroindole, indazole, N-formylindole,benzimidazole, thiazole, pyrimidine, and thiadiazole.

[0151] The chemist of ordinary skill will recognize that certaincombinations of heteroatom-containing substituents listed in thisinvention define compounds which will be less stable under physiologicalconditions (e.g., those containing acetal or aminal linkages).Accordingly, such compounds are less preferred.

[0152] The expression “prodrug” refers to compounds that are drugprecursors, which following administration, release the drug in vivo viasome chemical or physiological process (e.g., a prodrug on being broughtto the physiological pH is converted to the desired drug form).Exemplery prodrugs upon cleavage release the corresponding free acid,and such hydrolyzable ester-forming residues of the compounds of thisinvention include but are not limited to carboxylic acid substituents(e.g., R¹ is —(CH₂)_(q)C(O)₂X⁶ where X⁶ is hydrogen, or R² or A¹contains carboxylic acid) wherein the free hydrogen is replaced by(C₁-C₄)alkyl, (C₂-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyl-oxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[0153] Other exemplary prodrugs release an alcohol of formula I whereinthe free hydrogen of the hydroxyl substituent (e.g., R¹ containshydroxyl) is replaced by (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyl- oxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N-(C₁-C₆)alkoxycarbonylamino-methyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacetyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacylmoieties are independently any of the naturally occurring L-amino acidsfound in proteins, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (theradical resulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

[0154] Prodrugs of compounds of formula I where a carboxyl group in acarboxylic acid of formula I is replaced by an ester may be prepared bycombining the carboxylic acid with the appropriate alkyl halide in thepresence of a base such as potassium carbonate in an inert solvent suchas DMF at a temperature of about 0° C. to 100° C. for about 1 to about24 hours. Alternatively, the acid is combined with the appropriatealcohol as solvent in the presence of a catalytic amount of acid such asconcentrated sulfuric acid at a temperature of about 20° C. to 120° C.,preferably at reflux, for about 1 hour to about 24 hours. Another methodis the reaction of the acid in an inert solvent such as THF, withconcomitant removal of the water being produced by physical (e.g., DeanStark trap) or chemical (e.g., molecular sieves) means.

[0155] Prodrugs of compounds of formula I where an alcohol function hasbeen derivatized as an ether may be prepared by combining the alcoholwith the appropriate alkyl bromide or iodide in the presence of a basesuch as potassium carbonate in an inert solvent such as DMF at atemperature of about 0° C. to 100° C. for about 1 to about 24 hours.Alkanoylaminomethyl ethers may be obtained by reaction of the alcoholwith a bis-(alkanoylamino)methane in the presence of a catalytic amountof acid in an inert solvent such as THF, according to a method describedin U.S. Pat. No. 4,997,984. Alternatively, these compounds may beprepared by the methods described by Hoffman et al. in J. Org. Chem.1994, 59, p. 3530.

[0156] Certain of the above defined terms may occur more than once inthe above formula and upon such occurrence each term shall be definedindependently of the other.

[0157] Throughout the specification and appendent claims the followingabbreviations are used with the following meanings: BOCt-butyloxycarbonyl BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate CBZ Benzyloxycarbonyl CDIN,N′-Carbonyldiimidazole CH₂Cl₂ Methylene chloride CHCl₃ Chloroform DCCDicyclohexylcarbodiimide DMF Dimethylformamide EDC1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride EtOAc Ethylacetate FMOC 9-Fluorenylmethoxycarbonyl h hours Hex Hexane HOAT1-Hydroxy-7-azabenzotriazole HOBT Hydroxybenzotriazole hydrate HPLC Highpressure liquid chromatography MHz Megahertz MS Mass Spectrum NMRNuclear Magnetic Resonance PTH Parathyroid hormone TFA Trifluoroaceticacid THF Tetrahydrofuran TLC Thin layer chromatography TRH Thyrotropinreleasing hormone TROC 2,2,2-Trichloroethoxycarbonyl

[0158] The compounds utilized in a method of the instant invention allhave at least one asymmetric center as noted by the asterisk in thestructural formula I, above. Additional asymmetric centers may bepresent on the molecule depending upon the nature of the varioussubstituents on the molecule. Each such asymmetric center will producetwo optical isomers and it is intended that all such optical isomers, asseparated, pure or partially purified optical isomers, racemic mixturesor diastereomeric mixtures thereof, be included within the scope of theinstant invention. In the case of the asymmetric center represented bythe asterisk, it has been found that the absolute stereochemistry of themore active and, thus, more preferred isomer is shown in formula IA.This preferred absolute configuration also applies to formula I.

[0159] With the R⁴ substituent as hydrogen, the spatial configuration ofthe asymmetric center corresponds to that in a D-amino acid. In mostcases this is also designated an R-configuration although this will varyaccording to the values of R³ and R⁴ used in making R- orS-stereochemical assignments.

[0160] The compounds of formula I utilized in methods of the instantinvention are generally isolated in the form of their pharmaceuticallyacceptable acid addition salts, such as the salts derived from usinginorganic and organic acids. Examples of such acids are hydrochloric,nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic,propionic, maleic, succinic, D-tartaric, L-artaric, malonic, methanesulfonic and the like. In addition, certain compounds containing anacidic function such as a carboxy can be isolated in the form of theirinorganic salt in which the counter-ion can be selected from sodium,potassium, lithium, calcium, magnesium and the like, as well as fromorganic bases.

[0161] The pharmaceutically acceptable salts are formed by taking about1 equivalent of a compound of formula I and contacting it with about 1equivalent of the appropriate corresponding acid of the salt which isdesired. Work-up and isolation of the resulting salt is well-known tothose of ordinary skill in the art.

[0162] The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, an insulin resistancetreating amount of at least one of the compounds of formula I inassociation with a pharmaceutically acceptable carrier. Further, thepresent invention includes within its scope pharmaceutical compositionscomprising, as an active ingredient, at least one alpha-2 adrenergicagonist and at least one of the compounds of formula I in associationwith a pharmaceutically acceptable carrier. Optionally, thepharmaceutical compositions can further comprise an anabolic agent inaddition to at least one of the compounds of formula I or anothercompound which exhibits a different activity, e.g., an antibiotic growthpermittant or with other pharmaceutically active materials wherein thecombination enhances efficacy and minimizes side effects.

[0163] Assay for Stimulation of GH Release from Rat Pituicytes

[0164] Compounds that have the ability to stimulate GH secretion fromcultured rat pituitary cells are identified using the followingprotocol. This test is also useful for comparison to standards todetermine dosage levels. Cells are isolated from pituitaries of 6-weekold male Wistar rats. Following decapitation, the anterior pituitarylobes are removed into cold, sterile Hank's balanced salt solutionwithout calcium or magnesium (HBSS). Tissues are finely minced, thensubjected to two cycles of mechanically assisted enzymatic dispersionusing 10 U/mL bacterial protease (EC 3.4.24.4, Sigma P-6141, St. Louis,Mo.) in HBSS. The tissue-enzyme mixture is stirred in a spinner flask at30 rpm in a 5% CO₂ atmosphere at about 37° C. for about 30 min., withmanual trituration after about 15 min. and about 30 min. using a 10-mLpipet. This mixture is centrifuged at 200× g for about 5 min. Horseserum (35% final concentration) is added to the supernatant toneutralize excess protease. The pellet is resuspended in fresh protease(10 U/mL), stirred for about 30 min. more under the previous conditions,and manually triturated, ultimately through a 23-gauge needle. Again,horse serum (35% final concentration) is added, then the cells from bothdigests are combined, pelleted (200× g for about 15 min.), resuspendedin culture medium (Dulbecco's Modified Eagle Medium (D-MEM) supplementedwith 4.5 g/L glucose, 10% horse serum, 2.5% fetal bovine serum, 1%non-essential amino acids, 100 U/mL nystatin and 50 mg/mL gentamycinsulfate, Gibco, Grand Island, N.Y.) and counted. Cells are plated at6.0-6.5×10⁴ cells per cm² in 48-well Costar™ (Cambridge, Mass.) dishesand cultured for 3-4 days in culture medium.

[0165] Just prior to GH secretion assay, culture wells are rinsed twicewith release medium, then equilibrated for about 30 minutes in releasemedium (D-MEM buffered with 25 mM Hepes, pH 7.4 and containing 0.5%bovine serum albumin at 37° C.). Test compounds are dissolved in DMSO,then diluted into pre-warmed release medium. Assays are run inquadruplicate. The assay is initiated by adding 0.5 mL of release medium(with vehicle or test compound) to each culture well. Incubation iscarried out at about 37° C. for about 15 minutes, then terminated byremoval of the release medium, which is centrifuged at 2000× g for about15 minutes to remove cellular material. Rat growth hormoneconcentrations in the supernatants are determined by a standardradioimmunoassay protocol described below.

[0166] Measurement of Rat Growth Hormone

[0167] Rat growth hormone concentrations were determined by doubleantibody radioimmunoassay using a rat growth hormone referencepreparation (NIDDK-rGH-RP-2) and rat growth hormone antiserum raised inmonkey (NIDDK-anti-rGH-S-5) obtained from Dr. A. Parlow (Harbor-UCLAMedical Center, Torrence, Calif.). Additional rat growth hormone(1.5U/mg, #G2414, Scripps Labs, San Diego, Calif.) is iodinated to aspecific activity of approximately 30 μCi/μg by the chloramine T methodfor use as tracer. Immune complexes are obtained by adding goatantiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) plus polyethyleneglycol, MW 10,000-20,000 to a final concentration of 4.3%; recovery isaccomplished by centrifugation. This assay has a working range of0.08-2.5 μg rat growth hormone per tube above basal levels.

[0168] Assay for Exogenously-Stimulated Growth Hormone Release in theRat After Intravenous Administration of Test Compounds

[0169] Twenty-one day old female Sprague-Dawley rats (Charles RiverLaboratory, Wilmington, Mass.) are allowed to acclimate to localvivarium conditions (24° C., 12 hr light, 12 hr dark cycle) forapproximately 1 week before compound testing. All rats are allowedaccess to water and a pelleted commercial diet (Agway Country Food,Syracuse N.Y.) ad libitum. The experiments are conducted in accordancewith the NIH Guide for the Care and Use of Laboratory Animals.

[0170] On the day of the experiment, test compounds are dissolved invehicle containing 1% ethanol, 1 mM acetic acid and 0.1% bovine serumalbumin in saline. Each test is conducted in three rats. Rats areweighed and anesthetized via intraperitoneal injection of sodiumpentobarbital (Nembutol®, 50 mg/kg body weight). Fourteen minutes afteranesthetic administration, a blood sample is taken by nicking the tip ofthe tail and allowing the blood to drip into a microcentrifuge tube(baseline blood sample, approximately 100 μl). Fifteen minutes afteranesthetic administration, test compound is delivered by intravenousinjection into the tail vein, with a total injection volume of 1 mL/kgbody weight. Additional blood samples are taken from the tail at 5, 10and 15 minutes after compound administration. Blood samples are kept onice until serum separation by centrifugation (1430× g for 10 minutes at10° C.). Serum is stored at −80° C. until serum growth hormonedetermination by radioimmunoassay as described above.

[0171] Assessment of Exogenously-Stimulated Growth Hormone Release inthe Dog After Oral Administration

[0172] On the day of dosing, the test compound is weighed out for theappropriate dose and dissolved in water. Doses are delivered at a volumeof 0.5-3 mL/kg by gavage to 2-4 dogs for each dosing regimen. Bloodsamples (5 mL) are collected from the jugular vein by direct venapuncture pre-dose and at 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8 and 24hours post dose using 5 mL vacutainers containing lithium heparin. Theprepared plasma is stored at −20° C. until analysis.

[0173] Measurement of Canine Growth Hormone

[0174] Canine growth hormone concentrations are determined by a standardradioimmunoassay protocol using canine growth hormone (antigen foriodination and reference preparation AFP-1983B) and canine growthhormone antiserum raised in monkey (AFP-21452578) obtained from Dr. A.Parlow (Harbor-UCLA Medical Center, Torrence, Calif.). Tracer isproduced by chloramine T-iodination of canine growth hormone to aspecific activity of 20-40 μCi/μg. Immune complexes are obtained byadding goat antiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) pluspolyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%;recovery is accomplished by centrifugation. This assay has a workingrange of 0.08-2.5 μg canine GH/tube.

[0175] Assessment of Canine Growth Hormone and Insulin-Like GrowthFactor-1 Levels in the Dog After Chronic Oral Administration

[0176] The dogs receive test compound daily for either 7 or 14 days.Each day of dosing, the test compound is weighed out for the appropriatedose and dissolved in water. Doses are delivered at a volume of 0.5-3ml/kg by gavage to 5 dogs for each dosing regimen. Blood samples arecollected at days 0, 3, 7, 10 and 14. Blood samples (5 ml) are obtainedby direct venipuncture of the jugular vein at pre-dose, 0.17, 0.33, 0.5,0.754, 1, 2, 3, 6, 8, 12 and 24 hours post administration on days 0, 7and 14 using 5 ml vacutainers containing lithium heparin. In addition,blood is drawn pre-dose and 8 hours on days 3 and 10. The preparedplasma is stored at −20° C. until analysis.

[0177] Female Rat Study

[0178] This study evaluates the effect of chronic treatment with a GHRPmimetic on weight, body composition and non-fasting plasmaconcentrations of glucose, insulin, lactate and lipids inestrogen-deficient and estrogen-replete female rats. Acuteresponsiveness of serum GH levels to i.v. administration of the GHreleasing agent was assessed on the last day of dosing. Body weight wasmonitored weekly throughout the treatment period; additionally, bodycomposition and plasma levels of glucose, insulin, lactate, cholesteroland triglycerides were assessed at the end of treatment.

[0179] Virgin female Sprague-Dawley rats were obtained from CharlesRiver Laboratories (Wilmington, Mass.) and underwent bilateralovariectomy (Ovx) or sham-surgery (Sham) at approximately 12 weeks ofage. For sham surgeries, ovaries were exteriorized and replaced into theabdominal cavity. Following surgery the rats were housed individually in20 cm×32 cm×20 cm cages under standard vivarium conditions (about 24° C.with about 12 hours light/12 hours dark cycle). All rats were allowedfree access to water and a pelleted commercial diet (Agway ProLab 3000,Agway Country Food, Inc., Syracuse, N.Y.). The experiment was conductedin accordance with NIH Guidelines for the Care and Use of LaboratoryAnimals.

[0180] Approximately seven months post-surgery, Sham and Ovx rats wereweighed and randomly assigned to groups. Rats were dosed daily by oralgavage with 1 mL of either vehicle (1% ethanol in distilled-deionizedwater), 0.5 mg/kg or 5 mg/kg of a growth hormone releasing agent for 90days. Rats were weighed at weekly intervals throughout the study.Twenty-four hours after the last oral dose, the acute response of serumgrowth hormone (GH) to test agent was assessed by the followingprocedure. Rats were anesthetized with sodium pentobarbital 50 mg/kg.Anesthetized rats were weighed and a baseline blood sample (˜100 μl) wascollected from the tail vein. Test agent (growth hormone releasing agentor vehicle) was then administered intravenously via the tail vein in 1mL. Approximately ten minutes after injection, a second 100 μl bloodsample was collected from the tail. Blood was allowed to clot at about4° C., then centrifuged at 2000× g for about 10 minutes. Serum wasstored at about −70° C. Serum growth hormone concentrations weredetermined by radioimmunoassay as previously described. Following thisprocedure, each anesthetized rat underwent whole body scanning bydual-energy X-ray absorptiometry (DEXA, Hologic QDR 1000/W, WalthamMass.). A final blood sample was collected by cardiac puncture intoheparinized tubes. Plasma was separated by centrifugation and storedfrozen as described above.

[0181] Plasma insulin is determined by radioimmunoassay using a kit fromBinax Corp. (Portland, Me.). The interassay coefficient of variation is□ 10%. Plasma triglycerides, total cholesterol, glucose and lactatelevels are measured using Abbott VP™ and VP Super System® Autoanalyzer(Abbott Laboratories, Irving, Tex.), using the A-Gent™ Triglycerides,Cholesterol and Glucose Test reagent systems, and a lactate kit fromSigma, respectively. The plasma insulin, triglycerides, totalcholesterol and lactate lowering activity of a growth hormone releasingpeptide (GHRP) or GHRP mimetic such as a compound of formula I, aredetermined by statistical analysis (unpaired t-test) with thevehicle-treated control group.

[0182] The compounds of formula I utilized in a method of this inventioncan be administered by oral, parenteral (e.g., intramuscular,intraperitoneal, intravenous or subcutaneous injection, or implant),nasal, vaginal, rectal, sublingual, or topical routes of administrationand can be formulated with pharmaceutically acceptable carriers toprovide dosage forms appropriate for each route of administration.

[0183] Solid dosage forms for oral administration include capsules,tablets, pills, powders and granules. In such solid dosage forms, theactive compound is admixed with at least one inert pharmaceuticallyacceptable carrier such as sucrose, lactose, or starch. Such dosageforms can also comprise, as is normal practice, additional substancesother than such inert diluents, e.g., lubricating agents such asmagnesium stearate. In the case of capsules, tablets and pills, thedosage forms may also comprise buffering agents. Tablets and pills canadditionally be prepared with enteric coatings.

[0184] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,the elixirs containing inert diluents commonly used in the art, such aswater. Besides such inert diluents, compositions can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,and sweetening, flavoring and perfuming agents.

[0185] Preparations according to this invention for parenteraladministration include sterile aqueous or non-aqueous solutions,suspensions, or emulsions. Examples of non-aqueous solvents or vehiclesare propylene glycol, polyethylene glycol, vegetable oils, such as oliveoil and corn oil, gelatin, and injectable organic esters such as ethyloleate. Such dosage forms may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. They may be sterilized by,for example, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

[0186] Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as coca butter or a suppository wax.

[0187] Compositions for nasal or sublingual administration are alsoprepared with standard excipients well known in the art.

[0188] The dosage of active ingredient in the compositions of thisinvention may be varied; however, it is necessary that the amount of theactive ingredient be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment.Generally, dosage levels of between 0.0001 to 100 mg/kg of body weightdaily are administered to humans and other animals, e.g., mammals, toobtain effective release of growth hormone.

[0189] A preferred dosage range in humans is 0.01 to 5.0 mg/kg of bodyweight daily which can be administered as a single dose or divided intomultiple doses.

[0190] A preferred dosage range in animals other than humans is 0.01 to10.0 mg/kg of body weight daily which can be administered as a singledose or divided into multiple doses. A more preferred dosage range inanimals other than humans is 0.1 to 5 mg/kg of body weight daily whichcan be administered as a single dose or divided into multiple doses.

[0191] The preparation of the compounds of formula I utilized in amethod of the present invention can be carried out in sequential orconvergent synthetic routes. Syntheses detailing the preparation of thecompounds of formula I in a sequential manner are presented in thereaction schemes shown hereinbelow.

[0192] Many protected amino acid derivatives are commercially available,where the protecting groups Prt, Z¹⁰⁰ and Z²⁰⁰ are, for example, BOC,CBZ, benzyl, ethoxycarbonyl groups, CF₃C(O)—, FMOC, TROC, trityl ortosyl. Other protected amino acid derivatives can be prepared byliterature methods. Some 3-oxo-2-carboxyl pyrrolidines, and4-oxo-3-carboxyl piperidines are commercially available, and many otherrelated pyrrolidines and 4-substituted piperidines are known in theliterature.

[0193] Many of the schemes illustrated below describe compounds whichcontain protecting groups Prt, Z¹⁰⁰ or Z²⁰⁰. Benzyloxycarbonyl groupscan be removed by a number of methods including, catalytic hydrogenationwith hydrogen in the presence of a palladium or platinum catalyst in aprotic solvent such as methanol. Preferred catalysts are palladiumhydroxide on carbon or palladium on carbon. Hydrogen pressures from1-1000 psi may be employed; pressures from 10 to 70 psi are preferred.Alternatively, the benzyloxycarbonyl group can be removed by transferhydrogenation.

[0194] Removal of BOC protecting groups can be carried out using astrong acid such as trifluoroacetic acid or hydrochloric acid with orwithout the presence of a cosolvent such as dichloromethane, ethylacetate, ether or methanol at a temperature of about −30 to 70° C.,preferably about −5 to about 35° C.

[0195] Benzyl esters of amines can be removed by a number of methodsincluding, catalytic hydrogenation with hydrogen in the presence of apalladium catalyst in a protic solvent such as methanol. Hydrogenpressures from 1-1000 psi may be employed; pressures from 10 to 70 psiare preferred. The addition and removal of these and other protectinggroups are discussed by T. Greene in Protective Groups in OrganicSynthesis, John Wiley & Sons, New York, 1981.

[0196] Scheme 1: The protected amino acid derivatives 1 are in manycases commercially available, where the protecting group Prt is, forexample, BOC, FMOC or CBZ groups. Other amino acids can be prepared byliterature methods.

[0197] As illustrated in Scheme 1, coupling of amines of formula 2 withprotected amino acids of formula 1, where Prt is a suitable protectinggroup, is conveniently carried out in an inert solvent such asdichloromethane or DMF by a coupling reagent such as EDC or DCC in thepresence of HOBT or HOAT. In the case where the amine is present as thehydrochloride salt, it is preferable to add one or two equivalents of asuitable base such as triethylamine to the reaction mixture.Alternatively, the coupling can be effected with a coupling reagent suchas BOP in an inert solvent such as methanol. Such coupling reactions aregenerally conducted at temperatures of about −300 to about 80° C.,preferably −100 to about 25° C. For a discussion of other conditionsused for coupling peptides see Houben-Weyl, Vol. XV, part II, E. Wunsch,Ed., George Theime Verlag, 1974, Stuttgart. Separation of unwanted sideproducts and purification of intermediates is achieved by chromatographyon silica gel, employing flash chromatography (W. C. Still, M. Kahn andA. Mitra, J. Org. Chem. 43 2923 1978), by crystallization or bytrituration.

[0198] Transformation of the compound of formula 3 into intermediates offormula 4 can be carried out by removal of the protecting group Prt asdescribed above. Coupling of intermediates of formula 4 to amino acidsof formula 5 can be effected as described above to give intermediates offormula 6. Deprotection of the amine 6 affords compounds of formula 7.

[0199] Scheme 2: Alternatively, compounds of formula 7 can be preparedby a convergent route as shown in Scheme 2. Intermediate esters offormula 8 can be prepared by treating amino acids 1, where Prt is asuitable protecting group, with a base such as potassium carbonatefollowed by an alkyl halide such as iodomethane in a suitable solventsuch as DMF. Deprotection of the amine transforms 8 into 9.Alternatively, many amino acids of formula 9 are commercially available.Intermediate 10 is generated by coupling 9 to amino acid 5. The ester ofintermediate 10 can be converted to intermediate acid 11 by a number ofmethods known in the art; for example, methyl and ethyl esters can behydrolyzed with lithium hydroxide in a protic solvent such as aqueousmethanol or aqueous THF at a temperature of about −20° to 120° C.,preferably about 0° to 50° C. In addition, removal of a benzyl group canbe accomplished by a number of reductive methods including hydrogenationin the presence of platinum or palladium catalyst in a protic solventsuch as methanol. Acid 11 can then be coupled to amine 2 to giveintermediates of formula 6. Transformation of 6 to 7 can be achieved byremoval of the protecting group Z²⁰⁰.

[0200] Scheme 3: The esters of formula 6 can be converted tointermediate acids of formula 13 by a number of methods known in theart; for example, methyl and ethyl esters can be hydrolyzed with lithiumhydroxide in a protic solvent such as aqueous methanol or aqueous THF ata temperature of about −20° to 120° C., preferably about 0° to 50° C. Inaddition, removal of a benzyl group can be accomplished by a number ofreductive methods including hydrogenation in the presence of platinum orpalladium catalyst in a protic solvent such as methanol. Coupling theacid 13 to amine 16 generates the intermediates of formula 14.Transformation of 14 to 15 can be achieved by removal of the protectinggroup Z²⁰⁰.

[0201] Scheme 4: Esters of formula 17 can be prepared by treating anacid of formula 5 with hydroxysuccinimide in the presence of a couplingagent such as EDC in an inert solvent such as methylene chloride asillustrated in Scheme 4. Treatment of an ester 17 with an amino acid offormula 1 in a solvent such as dioxane, THF or DMF in the presence of abase such as duisopropylethylamine produces 11.

[0202] Scheme 5: As illustrated in Scheme 5, alkylation of thediphenyloxazinone of formula 18 with dinnamyl bromide in the presence ofsodium bis(trimethylsilyl)amide generates 19 which is then converted tothe desired (D)-2-amino-5-phenylpentanoic acid 20 by removing theprotecting group (Prt) and hydrogenation over a PdCl₂ catalyst.

[0203] Scheme 6: Treatment of an ester of formula 21 with a base such assodium hydride in a solvent such as DMF followed by an alkyl halide 22generates a compound of formula 23 as illustrated in Scheme 6. Treatinga compound of formula 23 with a hydrazine of formula 24 such ashydrazine or methyl-hydrazine in a solvent such as refluxing ethanol,followed by concentration and heating the residue in toluene attemperatures at or near reflux results in a compound of formula 25.Alternatively, 23 can be treated with a salt of a hydrazine in thepresence of sodium acetate in refluxing ethanol to give 25. Deprotectionof the amine generates a compound of formula 28. Thioamides of formula26 can be formed by treating 25 with Lawesson's reagent in refluxingtoluene or benzene. Removal of the protecting group transforms 26 into27.

[0204] Scheme 7: Treatment of a compound of formula 21 with a hydrazineof formula 24 in a solvent such as refluxing ethanol, followed byconcentration and heating the residue in toluene at temperatures at ornear reflux results in compounds of formula 29. Alternatively, 21 can betreated with a salt of a hydrazine in the presence of sodium acetate inrefluxing ethanol to give 29. The amide of formula 29 can be treatedwith a base such as sodium hydride in a solvent such as DMF followed byan alkyl halide to give 25. Deprotection of the amine generates acompound of formula 28.

[0205] Scheme 8: Reaction of a ketoester of formula 30 with a chiralamine such as alpha-methylbenzylamine with a suitable aldehyde such asformaldehyde, or reaction of a vinyl ketoester of formula 31 with achiral amine such as alpha-methylbenzylamine with a suitable aldehydesuch as formaldehyde, affords a compound of formula 32 via a doubleMannich reaction. Reaction of 32 with a hydrazine generates a chiralcompound of formula 33. Deprotection of the nitrogen with hydrogen and asuitable catalyst such as palladium affords compounds of formula 34.

[0206] Scheme 9: Treatment of a compound of formula 81 with a reducingagent such as sodium borohydride and protection of the nitrogen affordsa compound of formula 82. Protection of the alcohol affords 83.Saponification of the ester affords a compound of formula 84. Reactionof 84 with thionyl chloride followed by treatment with diazomethaneaffords the homologated acid of formula 85. Esterification of 85 affordsa compound of formula 86, which is O-deprotected to give 87. Oxidationof 87 affords a ketone of formula 88. Reaction of 88 with a hydrazine,followed by nitrogen deprotection affords a compound of formula 44.

[0207] Scheme 10: Treatment of a compound of formula 35 with a base suchas sodium hydride in a solvent such as DMF followed by treatment withdiethylcarbonate generates the ethyl ester of compound 36. Deprotectionof the amine transforms 36 into 37.

[0208] Scheme 11: Treatment of a malonic ester of formula 38 with a basesuch as sodium hydride in a solvent such as DMF and subsequenthydrogenolysis of the benzyl group with hydrogen and a catalyst such aspalladium in a suitable solvent such as methanol produces the ester offormula 39. Deprotection of the amine generates compounds of formula 40.

[0209] Scheme 12: Treatment of a ketone of formula 41 with a secondaryamine such as piperidine in a suitable solvent such as benzene withremoval of water affords an enamine of formula 42. Alkylation of theenamine with an alpha-haloester such as ethylbromoacetate in a suitablesolvent such as benzene or THF using a suitable base such as LDA orNaN(SiMe₃)₂ affords a ketoester of formula 43. Reaction with a hydrazineof formula 24 affords the compound of formula 44. Deprotection of thenitrogen affords compounds of formula 45.

[0210] Scheme 13: Treatment of a ketoester of formula 37 with aniodonium salt such as diphenyliodonium trifluoroacetate in a suitablesolvent such as t-butanol generates a ketoester of formula 46. Reactionof 46 with a hydrazine generates a compound of formula 47. Deprotectionof the nitrogen affords compounds of formula 48, see Synthesis, (9),1984 p. 709 for a detailed description.

[0211] Scheme 14: Treatment of a ketoester of formula 37 with an olefinsuch as acrylonitrile generates a ketoester of formula 49. Reaction of49 with a hydrazine generates a compound of formula 50. Deprotection ofthe nitrogen affords compounds of formula 51.

[0212] Scheme 15: Treatment of a ketoester of formula 37 with allylbromide and a suitable base such as sodium hydride in a suitable solventsuch as DMF affords a ketoester of formula 52. Reaction of 52 with ahydrazine generates a compound of formula 53. Ozonolysis of 53 in asuitable solvent such as methylene chloride followed by treatment with areducing agent such as dimethylsulfide affords an aldehyde of formula54. Oxidation of 54 affords a carboxylic acid of formula 55. Curtiusrearrangement of 55, followed by hydrolysis of the intermediateisocyanate affords a primary amine of formula 56. Treatment of acompound of formula 56 with an isocyanate or carbamate affords a urea offormula 57. Deprotection of the nitrogen affords compounds of formula58.

[0213] Scheme 16: Treatment of a compound of formula 54 with a primaryamine affords an imine of formula 59. Reduction of a compound of formula59 affords a compound of formula 60. Treatment of a compound of formula60 with an acylating agent affords a compound of formula 61.Deprotection of the nitrogen affords compounds of formula 62.

[0214] Scheme 17: Treatment of a compound of formula 54 with a reducingagent such as sodium borohydride affords a compound of formula 63.Reaction of 63 with an acylating agent such as an isocyanate orcarbamate affords compounds of formula 64. Deprotection of the nitrogenaffords compounds of formula 65.

[0215] Scheme 18: Treatment of a compound of formula 63 with a phosphinesuch as triphenyl phosphine and an azo compound such asdiethylazodicarboxylate and an oxindole affords a compound of formula66. Deprotection of the nitrogen affords the compound of formula 67.

[0216] Scheme 19: Treatment of a ketoester of formula 37 with a chiraldiol and acid catalyst with removal of water in a suitable solvent suchas benzene affords a chiral ketal of formula 68. Alkylation of 68 withan alkyl halide in the presence of a base such as LDA followed byacid-catalyzed hydrolysis of the ketal affords chiral ketoesters offormula 69. Reaction of 69 with a hydrazine generates chiral compoundsof formula 70. Deprotection of the nitrogen affords compounds of formula71.

[0217] Scheme 20: Treatment of a ketoester of formula 37 with a chiralamino acid ester such as valine t-butyl ester affords a chiral enamineof formula 72. Alkylation of 72 with an alkyl halide in the presence ofa base such as LDA followed by acid-catalyzed hydrolysis of the enamineaffords chiral ketoesters of formula 69. Reaction of 69 with a hydrazinegenerates chiral compounds of formula 70. Deprotection of the nitrogenaffords compounds of formula 71.

[0218] Scheme 21: Deprotection of the nitrogen of 25 affords compoundsof formula 28. Salt formation of 28 with a chiral acid affords a mixtureof diastereomeric salts of formula 73. Crystallization of thediastereomeric salts affords the acid salt of chiral compounds offormula 70. Decomposition of the salt 70 with base liberates chiralcompounds of formula 71.

[0219] Scheme 22: Alkylation of compounds of formula 25 with an allylicacetate in the presence of a suitable catalyst such as palladiumtetrakis(triphenylphosphine) affords compounds of formula 74.Deprotection of the nitrogen affords compounds of formula 75, seeTetrahedron (50) p. 515, 1994 for a detailed discussion.

[0220] Scheme 23: Treatment of a ketodiester of formula 76 with an alkylhalide in the presence of a base such as sodium hydride followed byacid-catalyzed hydrolysis and decarboxylation, followed byesterification with methyliodide and a suitable base affords a compoundof formula 77. Reaction of a compound of formula 77 with a suitablealdehyde such as formaldehyde and benzylamine affords a compound offormula 78. Reaction of a compound of formula 78 with a hydrazinegenerates chiral compounds of formula 79. Deprotection of the nitrogenaffords compounds of formula 80.

[0221] Scheme 24: Treatment of an amine of formula 23 with an acid offormula 11 in an inert solvent such as dichloromethane or DMF by acoupling reagent such as EDC or DCC in the presence of HOBT affordscompounds of formula 89. Reaction of compounds of formula 89 with ahydrazine generates compounds of formula 6. Deprotection of the nitrogenaffords compounds of formula 7.

[0222] Scheme 25: Treatment of a hydroxyacetoacetate ester of formula 90with an alkyl halide in the presence of a suitable base such as sodiumhydride affords compounds of formula 91. Reaction of 91 with a hydrazinegenerates compounds of formula 92. O-Alkylation of the carbonyl oxygenof 92 affords 93 which is converted to the halide 94. Displacement ofthe halide X by cyamide ion affords the nitrile 95. Reduction of 95gives the primary amine 96 which is deprotected and cyclized in thepresence of formaldehyde to afford 28.

[0223] Scheme 26: Treatment of a beta-keto-protected aminovalerate suchas 97 with an alkyl halide in the presence of a suitable base such assodium hydride affords compounds of formula 98. Reaction of compounds offormula 98 with a hydrazine generates compounds of formula 99.Deprotection of compounds of formula 99 affords primary amines offormula 100. Cyclization of compounds of formula 100 in the presence offormaldehyde affords compounds of formula 28.

[0224] Scheme 27: Treatment of the amine of formula 23a with an acidsuch as 1 in the presence of EDC and HOAT in a suitable solvent providesketo-esters of formula 23b. The keto-ester 23b can be treated with asalt of hydrazine in the presence of sodium acetate in refluxing ethanolto give hydrazines of formula 23c. Deprotection under suitableconditions gives amines of formula 4. Coupling of intermediates offormula 4 to amino acids of formula 5 can be effected as described aboveto give intermediates of formula 6. Deprotection of amine 6 affordscompounds of formula 7.

[0225] Scheme 28: Prt represents an amine protecting group that will beknown to one skilled in the art. BOC has been used for Prt to illustratethe preferred protecting group but the use of BOC should not be taken aslimiting the scope of this disclosure. Further, although the schemeillustrates the synthesis of the compound of formula m using particularisomers, other isomers and/or isomeric mixtures are also within thescope the instant disclosure.

[0226] Step A.

[0227] To a solution of 4-oxo-piperidine-3-carboxylic acid ethyl esterhydrochloride in a reaction inert organic solvent such as IPE, THF,methylene chloride and EtOAc with or without water as a cosolvent,preferably IPE and water, is added an inorganic or organic base such asTEA, DMAP, an hydroxide or a carbonate, preferably TEA, followed by anamine protecting group, preferably (Boc)₂O. The mixture is stirred forabout 1-24 hours, preferably overnight, preferably under nitrogen. Theorganic phase is separated and worked-up according to standardprocedures known to those skilled in the art, and concentrated to affordthe desired product as crystals.

[0228] Step B.

[0229] To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester in an organic solvent such as THF, IPE,an alcohol, DNF, or DMSO, preferably DMF, an inorganic or organic basesuch as TEA, DMAP, an hydroxide or a carbonate, preferably lithiumcarbonate, is added, followed by benzyl bromide. The mixture is heatedto about 25-100° C., preferably 60° C., and stirred for about 1-24hours, preferably 20 hours. The reaction mixture is then cooled to roomtemperature and extracted with an organic solvent such as IPE, toluene,THF or EtOAc and worked-up according to standard procedures known tothose skilled in the art to yield the desired compound.

[0230] Step C.

[0231] To a solution of 3-benzyl-4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester in an organic solvent such as analcohol, THF or toluene is added methylhydrazine, followed by an acidsuch as sulfuric acid, HCl, AcOH or TsOH, preferably acetic acid atabout 0° C. to room temperature. The reaction mixture is heated slowlyto about 40-100° C., preferably about 65° C. and stirred for about 3-10hours, preferably about 7.5 hours. After cooling to room temperature,the organic layer is washed with 10% sodium bicarbonate and worked-upaccording to standard procedures known to those skilled in the art andconcentrated to yield the desired compound.

[0232] Step D.

[0233] The concentrated solution from step C is mixed with an organicsolvent such as IPE, cooled to about −10-10° C., preferably 0° C., anacid such as MeSO₃H, TFA or HCl, preferably HCl gas, is introducedrepeatedly and stirred at room temperature until the hydrolysis iscomplete. The mixture is concentrated, an organic solvent such asmethylene chloride, IPE or THF is added, followed by a base such as ahydroxide, a carbonate, preferably NH₄OH. The mixture is then extractedwith methylene chloride, IPE or THF and concentrated to yield thedesired compound.

[0234] Step E.

[0235] To a solution of3a-benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onein a mixture of acetone/water (1% to 11% water, preferably 5% water inacetone) is added L-tartaric acid. The mixture is heated to 25-60° C.,preferably about 50° C., and stirred, preferably overnight. The reactionmixture is cooled to preferably about 10-15° C. and precipitates arefiltered, washed with cold acetone/water and dried to yield the desiredcompound.

[0236] Step G.

[0237] 2-Aminoisobutyric acid, a base such as a hydroxide, preferably 1NNaOH, (Boc)₂O and an organic solvent such as THF, IPE or dioxane aremixed together and stirred at room temperature overnight. The reactionmixture is diluted with organic solvent such as ethyl acetate andadjusted to about pH 3 to 7 by adding an aqueous acid such as HCl. Theorganic phase is separated and worked-up according to standardprocedures known to those skilled in the art to yield the desiredcompound.

[0238] Step H.

[0239] To a solution of 2-amino-3-benzyloxy-propionic acid in water andan inorganic or organic base, preferably TEA, is added2-tert-butoxycarbonylamino-2-methyl-propionic acid2,5-dioxo-pyrrolidin-1-yl ester in an organic solvent such as THF. Themixture is stirred preferably overnight at preferably room temperature,preferably under nitrogen. An aqueous acid such as 10% citric acidsolution is added to the mixture. The mixture is stirred for severalminutes, then diluted with an organic solvent such as ethyl acetate. Theorganic phase is separated from the mixture and worked-up according tostandard procedures known to those skilled in the art and thenconcentrated to yield the desired compound.

[0240] Steps F and I.

[0241] To a solution of3a-(R)-benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one,L-tartrate in organic solvent such as ethyl acetate at about −78 to −20°C., preferably about −66° C., is added a base such as TEA. The mixtureis stirred for 1-24 hours, preferably about 1.5 hours. After removal ofthe precipitated salt,3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid and a base such as TEA are added at about −50 to 0° C., preferablyabout −35° C., followed by the addition of a peptide coupling reagent,preferably 50% 1-propane phosphonic acid cyclic anhydride (PPAA) inethyl acetate. The mixture is stirred for about 1-6 hours, preferablyabout 2 hours at −50 to 0° C., preferably about −20° C. to about −27°C., then the temperature was slowly raised to preferably about 0° C. Thereaction mixture is poured into water and extracted with an organicsolvent such as IPE and the organic layer is separated and worked-upaccording to standard methods known to those skilled in the art to yieldthe desired compound.

[0242] Step J.

[0243] To a solution of{1-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester in an organic solvent such as methylene chlorideat about −10 to 10° C., preferably about 0-5° C. is added TFA,preferably the temperature is maintained below about 5° C. Thetemperature is then raised to room temperature. The mixture is stirredfor about 1-6 hours, preferably about 3 hours. Methylene chloride isreplaced with another organic solvent such as ethyl acetate. The mixtureis then adjusted to about pH 7 to pH 9, preferably pH 8, with an aqueousbase such as saturated sodium bicarbonate solution and then worked-upaccording to standard methods known to those skilled in the art to yieldthe desired compound.

[0244] Step K.

[0245] To a solution of2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamidefrom step I in an alcohol such as methanol is added L-(+)-tartaric acidand the mixture is stirred overnight. The resulting solution is filteredand concentrated. An organic solvent such as IPE or ethyl acetate isadded and the remaining alcohol is removed azeotropically. The solidthat is isolated is dissolved in ethyl acetate and the solution isrefluxed, then allowed to cool to room temperature to yield crystals ofthe desired product.

[0246] The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

[0247] General Experimental Procedures:

[0248] Amicon silica 30 μM, 60 Å pore size, was used for columnchromatography. Melting points were taken on a Buchi 510 apparatus andare uncorrected. Proton and carbon NMR spectra were recorded on a VarianXL-300, Bruker AC-300, Varian Unity 400 or Bruker AC-250 at 25° C.Chemical shifts are expressed in parts per million down field fromtrimethylsilane. Particle beam mass spectra were obtained on aHewlett-Packard 5989A spectrometer using ammonia as the source ofchemical ionization. For initial sample dissolution, chloroform ormethanol was employed. Liquid secondary ion mass spectra (LSIMS) wereobtained on a Kratos Concept-1S high resolution spectrometer usingcesium ion bombardment on a sample dissolved in a 1:5 mixture ofdithioerythritol and dithiothreitol or in a thioglycerol matrix. Forinitial sample dissolution chloroform or methanol was employed. Reporteddata are sums of 3-20 scans calibrated against cesium iodide. TLCanalyses were performed using E. Merck Kieselgel 60 F254 silica platesvisualized (after elution with the indicated solvent(s)) by stainingwith 15% ethanolic phosphomolybdic acid and heating on a hot plate.

[0249] General Procedure A (Peptide coupling using EDC): A 0.2-0.5 Msolution of the primary amine (1.0 equivalent) in dichloromethane (or aprimary amine hydrochloride and 1.0-1.3 equivalents of triethylamine) istreated sequentially with 1.0-1.2 equivalents of the carboxylic acidcoupling partner, 1.5-1.8 equivalents hydroxybenzotriazole hydrate(HOBT) or HOAT and 1.0-1.2 equivalents (stoichiometrically equivalent tothe quantity of carboxylic acid)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) andthe mixture is stirred overnight in an ice bath (the ice bath is allowedto warm, thus the reaction mixture is typically held at about 0-20° C.for about 4-6 h and about 20-25° C. for the remaining period). Themixture is diluted with ethyl acetate or other solvent as specified, andthe resulting mixture washed twice with 1 N NaOH, twice with 1 N HCl (ifthe product is not basic), once with brine, dried over Na₂SO₄, andconcentrated giving the crude product which is purified as specified.The carboxylic acid component can be used as the dicyclohexylamine saltin coupling to the primary amine or hydrochloride of the latter; in thiscase no triethylamine is employed.

EXAMPLE 1

[0250]2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramidehydrochloride and

[0251]2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramidehydrochloride

[0252] A. 4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-ethyl Ester

[0253] A mixture of 8.00 g (38.5 mmol) of 4-oxo-piperidine-3-carboxylicacid ethyl ester hydrochloride, 9.23 g (42.4 mmol) ofdi-tert-butyidicarbonate, and 3.89 g (38.5 mmol) of triethylamine in 150mL of THF was stirred at room temperature for about 72 h. The mixturewas concentrated and the residue was dissolved in ethyl acetate andwashed three times each with 10% aqueous HCl, saturated aqueous sodiumbicarbonate solution, and brine, dried over MgSO₄, and concentrated togive 10.0 g of 1A as a white solid. MS (Cl, NH₃) 272 (MH⁺).

[0254] B. 3-(R,S)-(4-Fluoro-benzyl)-4-oxo-piperidine-1,3-dicarboxylicAcid 1-tert-butyl Ester 3-ethyl Ester

[0255] To a solution of 2.00 g (7.4 mmol) 1A in 10 mL of DMF was added282 mg (7.4 mmol) of sodium hydride (60% oil dispersion) and the mixturewas stirred at room temperature for about 15 min. A solution of 1.39 g(7.4 mmol) 4-fluorobenzyl bromide in 7 mL of DMF was added to thestirring solution and the mixture was stirred for about 72 h at roomtemperature. The mixture was diluted with ethyl acetate and washed oncewith water and four times with brine, dried over MgSO₄, and concentratedto give 2.8 g of 1B. MS (Cl, NH₃) 380 (MH⁺).

[0256] C.3a-(R,S)-(4-Fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicAcid tert-butyl Ester

[0257] A mixture of 2.54 g (6.7 mmol) of 1B and 309 mg (6.7 mmol) ofmethylhydrazine in 100 mL of ethanol was heated at reflux for about 8 h.The mixture was concentrated and the residue was dissolved in 100 mLtoluene and heated at reflux for about 17 h. The mixture wasconcentrated and the residue was purified by silica gel chromatographyusing an elution gradient of (18:82 v/v ethyl acetate:hexane) to (75:25v/v ethyl acetate:hexane) to give 1.0 g of 1C as a clear colorless oil.MS (Cl, NH₃) 362 (MH⁺).

[0258] D.3a-(R,S)-(4-Fluoro-benzyl)-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onetrifluoroacetate

[0259] To 1.00 g (2.8 mmol) of 1C was added 10 mL of trifluoroaceticacid at about 0° C. and the mixture was stirred for about 1 h. Ethylacetate was added and the mixture was concentrated to give 1.0 g of 1D.MS (Cl, NH₃) 263 (MH⁺).

[0260] E.(R)-3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicAcid

[0261] To 1.83 g (6.2 mmol) of N-t-BOC-O-benzyl-D-serine in 35 mL of DMFwas added 1.02 g (7.4 mmol) of potassium carbonate followed by 0.92 g(6.5 mmol) of iodomethane. The mixture was stirred overnight at about24° C. under an atmosphere of nitrogen. The reaction mixture was dilutedwith 200 mL of water, and extracted three times with ethyl acetate. Thecombined organics were washed five times with water and once with brine,dried over MgSO₄ and concentrated. The crude(R)-3-benzyloxy-2-tert-butoxycarbonyl-amino-propionic acid methyl esterwas dissolved in 15 mL of cold trifluoroacetic acid at about 0° C. andthe mixture was stirred for about 2 h. The mixture was concentrated andthe residue was diluted with 1N NaOH and extracted three times withethyl acetate. The combined organic extracts were washed with brine anddried over Na₂SO₄ to give 0.84 g (4.02 mmol) of the resulting(R)-2-amino-3-benzyloxy-propionic acid methyl ester which was coupled to0.81 g (4.02 mmol) of N-t-BOC-α-methylalanine to give 1.80 g of(R)-3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid methyl ester. The crude product was dissolved in 20 mL of 4:1THF:water and a solution of 335 mg (7.98 mmol) of lithium hydroxidehydrate in 1 mL of water was added to the solution and the mixture wasstirred overnight at room temperature. The mixture was concentrated andthe residue was diluted with ethyl acetate and acidified with aqueousHCl and extracted three times with ethyl acetate. The organic extractswere combined and washed once with brine, dried over Na₂SO₄ andconcentrated to give 1.60 g of 1E as an oil which solidified onstanding. ¹H NMR (CDCl₃ 300 MHz) δ 7.30 (m, 5H), 7.10 (d, 1H), 5.07 (bs,1H), 4.68 (m, 1H), 4.53 (q, 2H) 4.09 (m, 1H), 3.68 (m, 1H), 1.3-1.5 (m,15H).

[0262] F.(1-{1(R)-Benzyloxymethyl-2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

[0263] According to the method outlines in General Procedure A, 193 mg(0.51 mmol) of 1D and 196 mg (0.51 mmol) of 1E were coupled to give amixture of diastereomers. The residue was purified by silica gelchromatography using an elution gradient of (1:1 v/v ethylacetate:hexane) to 100% ethyl acetate to give 60 mg of less polar 1Fisomer 1 and 100 mg of more polar 1F isomer 2. MS (Cl, NH₃) 624 (MH⁺)for both isomers.

[0264] G.2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl-2-oxo-ethyl}-isobutyramidehydrochloride

[0265] To 60 mg (0.10 mmol) of 1F isomer 1 in 10 mL of ethanol was added4 mL of concentrated HCl and the mixture was stirred at room temperaturefor about 2 h. The mixture was concentrated and the residue wasprecipitated from ethanol/hexane to give 50 mg of 1G isomer 1 as a whitepowder. MS (Cl, NH₃) 524 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.32 (m, 5H),7.12 (m, 2H), 6.91 (m, 2H), 5.15 (m, 1H), 4.54 (s, 2H), 3.78 (m, 2H)3.02(m, 7H), 2.66 (m, 2H), 1.57 (s, 6H).

[0266] H.2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}isobutyramidehydrochloride

[0267] To 100 mg (0.16 mmol) of 1F isomer 2 in 10 mL of ethanol wasadded 4 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 2 h. The mixture was concentrated and the residuewas precipitated from ethanol/hexane to give 60 mg of 1H isomer 2 as awhite powder. MS (Cl, NH₃) 524 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.32(m, 5H), 7.08 (m, 2H), 6.95 (m, 2H), 6.80 (m, 2H), 5.30 (m, 1H), 4.61(m, 3H), 3.80 (m, 2H), 2.58 (m, 3H), 1.58 (s, 6H).

EXAMPLE 2

[0268]2-Amino-N-[2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

[0269] A. (R)-2-Amino-3-[(1H-indol-3-yl)-propionic acid methyl ester

[0270] To 4.92 g (16.2 mmol) of N-α-t-BOC-D-tryptophan in 100 mL of DMFwas added 2.46 g (17.8 mmol) of potassium carbonate followed by 2.41 g(17.0 mmol) of iodomethane, and the mixture was stirred overnight at 24°C. under an atmosphere of nitrogen. The reaction mixture was dilutedwith water, and extracted three times with ethyl acetate. The combinedorganics were washed five times with 500 mL of water and once withbrine, dried over MgSO₄ and concentrated to give 4.67 g of a whitesolid. To the crude(R)-2-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionic acid methylester was added 15 mL of cold trifluoroacetic acid at about 0° C. andthe mixture was stirred for about 2 h. The mixture was concentrated andthe residue was diluted with 1N NaOH and extracted three times withethyl acetate. The combined organic extracts were washed with brine anddried over Na₂SO₄ to give (R)-2-amino-3-(1H-indol-3-yl)-propionic acidmethyl ester as an orange oil in quantitative yield.

[0271] B.(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionicAcid Methyl Ester.

[0272] The crude product from 2A 1.55 g (7.1 mmol) was coupled to 1.44 g(7.1 mmol) of N-t-BOC-α-methylalanine according to Procedure A to givean oil which was purified by silica gel chromatography using a gradientof 10%, 20%, 30%, 40% and 50% ethyl acetate in hexane to elute.Recovered 1.32 g of(R)-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionicacid methyl ester.

[0273] C.(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionicAcid

[0274] To a solution of 1.03 g (2.64 mmol) of 2B in 10 mL of THF wasadded 381 mg (9.1 mmol) of lithium hydroxide hydrate in 2 mL of waterand the mixture was stirred overnight at room temperature. Excess THFwas removed by evaporation, and the basic aqueous mixture was extractedthree times with ethyl acetate, and then acidified to pH 4 with diluteacetic or hydrochloric acid. The product was extracted with ethylacetate and the combined organic extracts were washed with brine, driedover MgSO₄ and evaporated to give 1.03 g of 2C as an orange foam. MS(Cl, NH₃) 390 (MH⁺). ¹H NMR (CDCl₃ 300 MHz) δ 7.61 (d, 1H), 7.48 (d,1H), 7.27 (t, 1H), 7.10 (t, 1H), 4.81 (bs, 1H), 3.35 (m, 1H), 1.49 (s,6H), 1.32 (s, 9H).

[0275] D.{1-[2-[3a-(R,S)-(4-Fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0276] According to the method outlined in General Procedure A, 193 mg(0.51 mmol) of 1D and 200 mg (0.51 mmol) of 2C were coupled and theresidue was purified by silica gel chromatography using an elutiongradient of (1:1 v/v ethyl acetate:hexane) to 100% ethyl acetate to give230 mg of 2D. MS (Cl, NH₃) 633 (MH⁺).

[0277] E.2-Amino-N-[2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramideHydrochloride

[0278] To 230 mg (0.36 mmol) of 2D in 10 mL of ethanol was added 4 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 2 h. The mixture was concentrated and the residue was precipitatedfrom ethanol/hexane to give 130 mg of 2E as a white powder. MS (Cl, NH₃)533 (MH⁺). ¹ HNMR (CD₃OD): (partial) δ 7.79 (d, 1H), 7.48 (m, 1H), 7.33(m, 2H), 7.19-6.77 (m, 7H), 6.54 (m, 1H), 5.17 (m, 1H), 4.02 (m, 1H),3.11-2.68 (m, 6H), 2.47 (m, 2H), 2.03 (m, 2H), 1.59 (m, 6H).

EXAMPLE 3

[0279]2-Amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide

[0280] A. 4-Oxo-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester3-methyl Ester

[0281] To a mixture of 7.00 g (36.2 mmol) of4-oxo-piperidine-3-carboxylic acid methyl ester and 8.82 g (72.3 mmol)of 4,4-dimethylaminopyridine in 200 mL of methylene chloride at about 0°C. was added a solution of 7.88 g (36.2 mmol) ofdi-tert-butyldicarbonate in 150 mL of methylene chloride over about 30min. The mixture was warmed to room temperature and then stirred forabout 17 h. The mixture was concentrated and the residue was dilutedwith chloroform and washed three times each with 10% aqueous HCl,saturated aqueous sodium bicarbonate solution and brine, dried overMgSO₄ and concentrated to give 9.18 g of a clear yellow oil.

[0282] B. 3-(R,S)-Benzyl-4-oxo-piperidine-1,3-dicarboxylic Acid1-tert-butyl Ester 3-methyl Ester

[0283] To a solution of 5.00 g (19.4 mmol) 3A in 10 mL of DMF was added745 mg (7.4 mmol) of sodium hydride (60% oil dispersion) and the mixturewas stirred at room temperature for about 15 min. A solution of 3.32 g(19.4 mmol) benzylbromide in 15 mL of DMF was added to the stirringsolution by cannula and the mixture was stirred for about 42 h at roomtemperature. The mixture was diluted with ethyl acetate and washed oncewith water and four times with brine, dried over MgSO₄, and concentratedto give 6.0 g of 3B as a yellow oil. MS (Cl, NH₃) 348 (MH⁺).

[0284] C.3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]-pyridine-5-carboxylicAcid tert-butyl Ester

[0285] A mixture of 4.00 g (11.5 mmol) of 3B and 530 mg (11.5 mmol) ofmethylhydrazine in 100 mL of ethanol was heated at reflux for about 8 h.The mixture was concentrated and the residue was dissolved in 100 mLtoluene and heated at reflux for about 17 h. The mixture wasconcentrated and the residue was purified by silica gel chromatographyusing an elution gradient of (15:85 v/v ethyl acetate:hexane) to (75:25v/v ethyl acetate:hexane) to give 2.6 g of 3C as a clear colorless oil.MS (Cl, NH₃) 344 (MH⁺).

[0286] D.3a-(R,S)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

[0287] To 2.60 g (7.6 mmol) of 3C was added 20 mL of trifluoroaceticacid at about 0° C. and the mixture was stirred for about 2.5 h. Ethylacetate was added and the solution was washed with 6N NaOH, dried overMgSO₄ and concentrated to give 1.8 g of 3D. MS (Cl, NH₃) 244 (MH⁺).

[0288] E.{1-[2-(3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-CarbamicAcid tert-butyl Ester

[0289] According to the method outlined in General Procedure A, 125 mg(4.6 mmol) of 3C and 1.75 g (0.51 mmol) of 2C were coupled and theresidue was purified by silica gel chromatography using an elutiongradient of (6:4 v/v ethyl acetate:hexane) to 7% methanol in ethylacetate to give 150 mg of 3E.

[0290] F.2-Amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramideHydrochloride

[0291] To 150 mg (0.24 mmol) of 3E in 15 mL of ethanol was added 5 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 3 h. The mixture was concentrated and the residue was crystallizedfrom ethanol/hexane to give 100 mg of 3F. MS (Cl, NH₃) 515 (MH⁺). ¹HNMR(CD₃OD): δ 7.20-6.91 (m, 9H), 6.56 (m, 1), 5.17 (m, 1H), 4.05 (m, 1H),2.96 (s, 3H), 2.62 (m, 1H), 2.38 (m, 1H), 2.06 (m, 2H), 1.61 (m, 8H).

EXAMPLE 4

[0292]2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride and2-Amino-N-[2-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0293] A.{1-[2-(3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0294] According to the method outlined in General Procedure A, 1.12 g(4.6 mmol) of 3C and 1.75 g (0.51 mmol) of 1E were coupled to give amixture of diastereomers. The residue was purified by silica gelchromatography using an elution gradient of (1:1 v/v ethylacetate:hexane) to 100% ethyl acetate to give 350 mg of less polar 4Aisomer 1 and 250 mg of more polar 4A isomer 2. MS (Cl, NH₃) 606 (MH⁺)for both isomers.

[0295] B.2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0296] To 250 mg (0.41 mmol) of 4A isomer 1 in 15 mL of ethanol wasadded 5 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 5 h. The mixture was concentrated and the residuewas precipitated from ethanol/hexane and dried under vacuum to give 130mg of 4B isomer 1. MS (Cl, NH₃) 506 (MH⁺).

[0297]¹HNMR (CD₃OD): δ 7.33 (m, 5H), 7.14 (m, 5H), 5.22 (m, 1H), 4.57(m, 3H), 3.80 (m, 2H) 3.14 (m, 1H), 3.04 (s, 3H), 2.96 (m, 2H), 2.61 (m,2H), 1.63 (m, 7H).

[0298] C.2-Amino-N-[2-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0299] To 250 mg (0.41 mmol) of 4A isomer 2 in 15 mL of ethanol wasadded 5 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 5 h. The mixture was concentrated and the residuewas precipitated from ethanol/hexane and dried under vacuum to give 120mg of 4C isomer 2. MS (Cl, NH₃) 506 (MH⁺).

[0300]¹HNMR (CD₃OD): δ 7.31 (m, 5H), 7.13 (m, 5H), 6.78 (m, 1H), 5.28(m, 1H), 4.62 (m, 3H), 3.81 (M, 2H), 3.14 (m, 1H), 2.62 (m, 3H), 1.58(m, 7H).

[0301] D.2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideMethanesulfonate

[0302] Saturated aqueous sodium bicarbonate was added to 3.60 g (6.6mmol) of 4B isomer 1 and the mixture was extracted with ethyl acetate.The organic layer was dried over MgSO₄ and concentrated. The residue wasdissolved in ethyl acetate, cooled to about 0° C. and 0.43 mL (6.6 mmol)of methane-sulfonic acid was added and the mixture was stirred for about0.5 h. Hexane (200 mL) was added to the solution and the mixture wasstirred for about 1 h and filtered to give 3.40 g of a white solid. Thesolid was recrystallized from 3% aqueous ethyl acetate to give 2.55 g of4D isomer 1 as a white crystalline solid. MS (Cl, NH₃) 506 (MH⁺).

EXAMPLE 5

[0303]2-Amino-N-[1-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramideHydrochloride and

[0304]2-Amino-N-[1-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramideHydrochloride

[0305] A. 2-Oxo-5,6-diphenyl-3-(3-phenyl-allyl)-morpholine-4-carboxylicAcid T-Butyl Ester

[0306] To an about −78° C. solution of 13.8 g (70.0 mmol) of cinnamylbromide and 4.94 g (14.0 mmol) oft-butyl-(2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholine carboxylate in 350mL of anhydrous THF was added 28 mL (28 mmol) of 1M sodiumbistrimethylsilylamide in THF. The mixture was stirred at about −78° C.for about 1.5 h and then poured into 750 mL of ethyl acetate. Themixture was washed twice with brine, dried over MgSO₄ and concentratedto give a yellow oil. The oil was stirred in 150 mL of hexane overnightand the precipitated solid was then collected by filtration to give 3.2g of 5A as a white solid.

[0307] B. 5(S), 6(R)-Diphenyl-3(R)-(3-phenyl-allyl)-morpholin-2-one

[0308] To 2.97 g (6.33 mmol) of 5A was added 20 mL of trifluoroaceticacid at about 0° C. and the mixture was stirred for about 2 h and thenconcentrated. The residue was dissolved in water and basified withaqueous NaOH until a pH of 10 was maintained. The mixture was extractedthree times with ethyl acetate and the combined organic extracts werewashed with brine, dried over MgSO₄ and concentrated to give an orangeoil which was purified by silica gel chromatography (10:90 v/v ethylacetate:hexane) to give 880 mg of 5B as a white solid.

[0309] C. 2-(R)-Amino-5-phenyl-pentanoic Acid

[0310] A mixture of 440 mg (1.19 mmol) of 5B and 120 mg of palladiumchloride in 20 mL of ethanol and 10 mL of THF was hydrogenated at 45psi. for about 16 h. The mixture was filtered through diatomaceous earthand concentrated, and the residue was triturated with ether to give 240mg of 5C as a white solid.

[0311] D. 2-tert-Butoxycarbonylamino-2-methyl-propionic Acid2,5-dioxo-pyrrolidin-1-yl Ester

[0312] To a slurry of 5.0 g (24.6 mmol) of N-t-BOC-α-methylalanine in13.5 mL of methylene chloride was added 3.40 g (29.6 mmol) ofN-hydroxysuccinimide and 5.65 g (29.6 mmol) of EDC. The slurry wasstirred for about 17 h at room temperature. The mixture was diluted withethyl acetate and washed twice each with water, saturated sodiumbicarbonate solution and brine. Dried over MgSO₄ and concentrated. Theproduct was purified by silica gel chromatography (1:1 v/v ethylacetate:hexanes) to give 5.2 g of the title compound of this part D as awhite solid.

[0313] E.(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-5-phenyl-pentanoicAcid

[0314] A mixture of 203 mg (1.05 mmol) of 5D, 378 mg (1.26 mmol) of 5Cand 434 mg (3.36 mmol) of diisopropylethylamine in 2 mL of DMF wasstirred over-night. The mixture was diluted with ethyl acetate andextracted twice with 1 N HCl. The aqueous phase was extracted once withethyl acetate. The pooled organic extracts were washed three times withwater and once with brine. The mixture was dried over MgSO₄ andconcentrated. The residue was purified by silica gel chromatographyusing 80% chloroform in hexane followed by 100% chloroform followed by10% methanol in chloroform to give 127 mg of 5E.

[0315] F.{1-[1-(3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butylcarbamoyl]-1-methyl-ethyl]-carbamicAcid tert-butyl Ester

[0316] According to the method outlined in General Procedure A, 130 mg(0.53 mmol) of 3C and 200 mg (0.53 mmol) of 5E were coupled to give amixture of diastereomers. The residue was purified by silica gelchromatography using an elution gradient of (1:1 v/v ethylacetate:hexane) to 100% ethyl acetate to give 40 mg of less polar 5Fisomer 1 and 40 mg of more polar 5F isomer 2. MS (Cl, NH₃) 604 (MH⁺) forboth isomers.

[0317] G.2-Amino-N-[1-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4.6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramidehydrochloride

[0318] To 40 mg (0.07 mmol) of 5F isomer 1 in 10 mL of ethanol was added4 mL of concentrated HCl and the mixture was stirred at room temperaturefor about 4 h. The mixture was concentrated and the residue wasprecipitated from methylene chloride/hexane and dried under vacuum togive 30 mg of 5G isomer 1. MS (Cl, NH₃) 504 (MH⁺). ¹HNMR (CD₃OD):(partial) δ 7.19 (m, 10H), 4.37 (m, 1H), 3.02 (m, 6H), 2.67 (m, 4H),1.83 (m, 4H), 1.62 (s, 6H), 1.28 (m, 1H).

[0319] H.2-Amino-N-[1-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramideHydrochloride

[0320] To 40 mg (0.07 mmol) of 5F isomer 2 in 10 mL of ethanol was added4 mL of concentrated HCl and the mixture was stirred at room temperaturefor about 4 h. The mixture was concentrated and the residue wasprecipitated from methylene chloride/hexane and dried under vacuum togive 30 mg of 5H isomer 2. MS (Cl, NH₃) 504 (MH⁺). ¹HNMR (CD₃OD):(partial) 7.25 (m, 9H), 6.88 (m, 1H), 3.04 (s, 3H), 2,71 (m, 4H), 2.48(m, 2H), 1.75 (m, 4H), 1.62 (m, 6H), 1.28 (m, 1H).

EXAMPLE 6

[0321]2-Amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0322] A.{1-[2-(3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0323] According to the method outlined in General Procedure A, 200 mg(0.82 mmol) of 3C and 320 mg (0.82 mmol) of 1E were coupled to give amixture of diastereomers. The residue was purified by silica gelchromatography using an elution gradient of (1:1 v/v ethylacetate:hexane) to 10% methanol in ethyl acetate to give 170 mg of 6A.

[0324] B.2-Amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0325] To 170 mg (0.28 mmol) of 6A in 20 mL of ethanol was added 5 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 2.5 h. The mixture was concentrated and the residue wasprecipitated from ethanolihexane to give 70 mg of 6B. MS (Cl, NH₃) 506(MH⁺). ¹HNMR (CD₃OD): δ 7.32 (m, 5H); 7.16 (m, 5H), 5.22 (m, 1H), 4.67(m, 1H), 4.55 (m, 2H), 3.79 m, 2H), 3.12 (m, 2H), 3.00 (m, 6H), 2.71 (m,3H), 1.56 (m, 8H).

EXAMPLE 7

[0326]2-Amino-N-[2-(3a-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramideHydrochloride

[0327] A.3a-(R,S)-Benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicAcid tert-butyl Ester

[0328] To 555 mg (1.60 mmol) of 3B in 27 mL of ethanol was added 240 mg(1.60 mmol) of ethylhydrazineoxalate and the mixture was heated atreflux for about 4 h. The mixture was concentrated and the residue waspurified by silica gel chromatography using an elution gradient of (10:1v/v hexane:ethyl acetate) to (3:7 v/v hexane:ethyl acetate) to give 357mg of 7A. MS (Cl, NH₃) 358 (MH⁺).

[0329] B.3a-(R,S)-Benzyl-2-ethyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

[0330] To 350 mg (0.98 mmol) of 7A in 3 mL of ethanol was added 1.5 mLof concentrated HCl and the mixture was stirred at room temperature forabout 2 h. The mixture was concentrated to give 257 mg of 7B. MS (Cl,NH₃) 258 (MH⁺).

[0331] C.{1-[2-(3a-(R,S)-Benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-CarbamicAcid tert-butyl Ester

[0332] According to the method outlined in General Procedure A, 82 mg(0.28 mmol) of 7B and 100 mg (0.26 mmol) of 2C were coupled and theresidue was purified by silica gel chromatography using an elutiongradient of 100% methylene chloride to 2% methanol in methylene chlorideto give 110 mg of 7C. MS (Cl, NH₃) 629 (MH⁺).

[0333] D.2-Amino-N-[2-(3a-(R,S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramideHydrochloride

[0334] To 100 mg (0.15 mmol) of 7C in 2 mL of ethanol was added 1 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 2 h. The mixture was concentrated to give 72 mg of 7D as acolorless foam. MS (Cl, NH₃) 529 (MH⁺).

EXAMPLE 8

[0335] 2-Amino-N-[2-(3a-(R)-benzyl-2-ethyl-3-oxo-2,3,3a0.4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride and

[0336]2-Amino-N-[2-(3a-(S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0337] A.{1-[2-(3a-Benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0338] According to the method outlined in General Procedure A, 85 mg(0.29 mmol) of 7B and 100 mg (0.26 mmol) of 1E were coupled to give amixture of diastereomers. The residue was purified by silica gelchromatography using an elution gradient of 100% methylene chloride to2% methanol in methylene chloride to give 6 mg of less polar 8A isomer 1and 11 mg of more polar 8A isomer 2. MS (Cl, NH₃) 620 (MH⁺) for bothisomers.

[0339] B.2-Amino-N-[2-(3a-(R)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0340] To 5.7 mg (0.009 mmol) of 8A isomer 1 in 1 mL of ethanol wasadded 0.4 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 3 h. The mixture was concentrated to give 4.7 mgof 8B isomer 1. MS (Cl, NH₃) 520 (MH⁺).

[0341]¹HNMR (CD₃OD): (partial) δ 7.41-7.05 (m, 10H), 5.20 (m, 1H), 4.61(m, 1H), 4.52 (s, 2H), 3.71 (m, 1H), 3.60 (m, 1H), 2.61 (m, 3H), 1.39(m, 9H).

[0342] C.2-Amino-N-[2-(3a-(S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-y)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0343] To 10 mg (0.016 mmol) of 8A isomer 2 in 1 mL of ethanol was added0.4 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 3 h. The mixture was concentrated to give 8 mg of8C isomer 2. MS (Cl, NH₃) 520 (MH⁺).

[0344]¹HNMR (CD₃OD): (partial) δ 7.43-7.00 (m, 10H), 6.81 (m, 1H), 5.32(m, 1H), 4.63 (m, 2H), 4.53 (m, 1H), 3.72 (m, 1H), 1.37 (m, 9H).

EXAMPLE 9

[0345]2-Amino-N-[2-(2-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0346] A.2-Benzyl-3-hydroxy-2,4,6,7-tetrahydro-pyrazolo[4.3-c]pyridine-5-carboxylicAcid tert-butyl Ester

[0347] A mixture of 800 mg (3.11 mmol) of 3B and 495 mg (3.11 mmol) ofbenzylhydrazine dihydrochloride and 423 mg (3.11 mmol) of sodium acetatetrihydrate in 15 mL of ethanol was heated at reflux for about 17 h. Themixture was concentrated and the residue was dissolved in 100 mL oftoluene and heated at reflux for about 48 h. The mixture was dilutedwith ethyl acetate and washed with brine, dried over MgSO₄ andconcentrated and the residue was purified by silica gel chromatographyusing 100% ethyl acetate followed by 5% methanol in methylene chlorideto give 530 mg of 9A as a light brown solid. MS (Cl, NH₃) 330 (MH⁺).

[0348] B. 2-Benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-ol

[0349] To 411 mg (1.24 mmol) of 3E in 30 mL of ethanol was added 10 mLof concentrated HCl and the mixture was stirred at room temperature forabout 30 min. The mixture was concentrated and the residue wascrystallized from methanol/ethyl acetate to give 353 mg of 9B. MS (Cl,NH₃) 230 (MH⁺).

[0350] C.{1-[2-(2-Benzyl-3-hydroxy-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-R-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0351] According to the method outlined in General Procedure A, 100 mg(0.38 mmol) of 9B and 145 mg (0.38 mmol) of 1E were coupled and theresidue was purified by silica gel chromatography (95:5 v/vmethanol:methylene chloride) to give 42 mg of 9C as a white solid. MS(Cl, NH₃) 592 (MH⁺).

[0352] D.2-Amino-N-[2-(2-benzyl-3-oxo-2,3,3a.4,6,7-hexahydro-pyrazolo[4.3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0353] To 42 mg (0.07 mmol) of 9D in 20 mL of ethanol was added 6 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 30 min. The mixture was diluted with ethanol concentrated and theresidue was precipitated from methanol/ethyl acetate to give 35 mg of 9Das a white solid. MS (Cl, NH₃) 492 (MH⁺). ¹HNMR (CD₃OD): (partial)7.41-7.16 (m, 10H), 5.19 (m, 3H), 4.48 (m, 4H), 3.88 (m, 1H), 3.74 (m,2H), 2.68 (m, 2H), 1.58 (m, 6H).

EXAMPLE 10

[0354]2-Amino-N-{2-[3a-(R)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-isobutyramideHydrochloride and

[0355]2-Amino-N-{2-[3a-(S)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-isobutyramideHydrochloride

[0356] A.3a-(R,S)-Benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicAcid tert-butyl Ester

[0357] A mixture of 840 mg (2.42 mmol) of 3B and 276 mg (2.42 mmol) of2,2,2-trifluoroethylhydrazine (70% in water) in 20 mL of ethanol washeated at reflux for about 5 h and then concentrated. The residue wasdissolved in 40 mL of toluene and heated at reflux for about 17 h. Themixture was concentrated and the residue was purified by silica gelchromatography (9:1 v/v hexane:ethyl acetate) to give 703 mg of 10A as ayellow oil. MS (Cl, NH₃) 412 (MH⁺).

[0358] B.3a-(R,S)-Benzyl-2-(2,2,2-trifluoro-ethyl)-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

[0359] To 600 mg (1.46 mmol) of 10A at about 0° C. was added 3 mL ofcold trifluoroacetic acid and the mixture was stirred for about 3 h,allowing the solution to reach room temperature as it did so. Themixture was concentrated and the residue was dissolved in water and thesolution was basified to pH 11 with 5N NaOH and then saturated withpotassium carbonate. The solution was extracted three times with ethylacetate and the combined organic extracts were washed with brine, driedover MgSO₄ and concentrated to give 345 mg of 10B as an opaque oil. MS(Cl, NH₃) 312 (MH⁺).

[0360] C.(1-[2-[3a-(R,S)-Benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicAcid tert-butyl Ester

[0361] According to the method outlined in General Procedure A, 137 mg(0.44 mmol) of 10B and 167 mg (0.44 mmol) of 1E were coupled to give amixture of diastereomers. The residue was purified by silica gelchromatography using an elution gradient 100% methylene chloride to 5%methanol in methylene chloride to give 128 mg of less polar 10C isomer 1and 63 mg of more polar 10C isomer 2. MS (Cl, NH₃) 674 (MH⁺) for bothisomers

[0362] D.2-Amino-N-[2-[3a-(R)-benzyl-3-oxo-2-(202,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideHydrochloride

[0363] To 120 mg (0.18 mmol) of 10C isomer 1 in 3.5 mL of ethanol wasadded 1.5 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 2 h. The mixture was concentrated to give 94 mg of10D isomer 1 as an off-white powder. MS (Cl, NH₃) 574 (MH⁺). ¹HNMR(CD₃OD): (partial) δ 7.31 (m, 5H), 7.18 (m, 5H), 5.21 (m, 1H), 4.57 (m,3H), 4.26 (m, 1H), 4.08 (m, 1H), 3.79 (m, 2H), 3.09 (m, 4H), 2.65 (m,2H), 1.63 (m, 6H).

[0364] E.2-Amino-N-{2-[3a-(S)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3.3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-isobutyramideHydrochloride

[0365] To 53 mg (0.079 mmol) of 10C isomer 2 in 3.5 mL of ethanol wasadded 1.5 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 2 h. The mixture was concentrated to give 41 mg of10E isomer 2 as a light yellow solid. MS (Cl, NH₃) 574 (MH⁺). ¹HNMR(CD₃OD): (partial) δ 7.33 (m, 5H), 7.15 (m, 4H), 6.81 (m, 1H), 5.30 (m,1H), 4.67 (m, 4H), 4.15 (m, 2H), 3.77 (m, 2H), 3.09 (m, 3H), 2.64 (m,3H), 1.58 (m, 6H).

EXAMPLE 11

[0366]2-Amino-N-[2-(3a-(R)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideMethanesulfonate and

[0367]2-Amino-N-[2-(3a-(S)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideMethanesulfonate

[0368] A.3a-(R,S)-Benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6.7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

[0369] To 2.07 g (5.95 mmol) of 14B in 40 mL of ethanol was added 0.97 g(7.7 mmol) of tert-butylhydrazine hydrochloride and 0.63 g (7.7 mmol) ofsodium acetate and the mixture was heated at about 70° C. for about 17h. The mixture was cooled and the solution decanted from the precipitateand concentrated. The residue was dissolved in 80 mL of toluene andheated at reflux for about 6 h. The mixture was concentrated and theresidue was purified by silica gel chromatography (9:1 v/v hexane:ethylacetate) to give 1.7 g of 11A. MS (Cl, NH₃) 386 (MH⁺).

[0370] B.3a-(R,S)-Benzyl-2-tert-butyl-2,3a,4,5.6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

[0371] To 535 mg (1.39 mmol) of 1 1A in 20 mL of methylene chloride wasadded 225 μL of methanesulfonic acid and the mixture was stirred forabout 1.5 h at room temperature. The mixture was diluted with ethylacetate and washed twice with 1N NaOH and once with brine, dried overNa₂SO₄ and concentrated to give 246 mg of 11B. MS (Cl, NH₃) 286 (MH⁺).

[0372] C.{1-[2-(3a-(R,S)-Benzyl-2-tert-butyl-3-oxo-2,3.3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0373] According to the method outlined in General Procedure A, 246 mg(0.86 mmol) of 11B and 328 mg of 14F were coupled to give a mixture ofdiastereomers. The residue was purified by silica gel chromatography(6:4 v/v hexane/ethyl acetate) to give 250 mg of less polar 11C isomer 1and 90 mg more polar 11C isomer 2. MS (Cl, NH₃) 648 (MH⁺) for bothisomers.

[0374] D.2-Amino-N-[2-(3a-(R)-benzyl-2-tert-butyl-3-oxo-2.3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideMethanesulfonate

[0375] To 210 mg (0.32 mmol) of 11C isomer 1 in 15 mL of methylenechloride at about 0° C. was added 28 μL (0.44 mmol) of methanesulfonicacid. The ice bath was removed and the mixture was stirred for about 3h, diluted with 15 mL of diethyl ether and the precipitated solid wascollected by filtration to give 100 mg of 11 D isomer 1. MS (Cl, NH₃)548 (MH⁺). ¹H NMR (CD₃OD): (partial) δ 7.33 (m, 5H), 7.27-7.07 (m, 5H),5.21 (m, 1H), 4.54 (m, 3H), 3.86 (m, 3H), 3.10 (m, 4H), 2.61 (s, 3H),1.62(m, 6H), 1.18 (s, 9H).

[0376] E.2-Amino-N-[2-(3a-(S)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideMethanesulfonate

[0377] To 85 mg (0.13 mmol) of 11C isomer 2 in 10 mL of methylenechloride at about 0° C. was added 21 μL (0.32 mmol) of methanesulfonicacid. The ice bath was removed and the mixture was stirred for about 3h, diluted with 20 mL of diethyl ether and the precipitated solid wascollected by filtration to give 46 mg of 11E isomer 2. MS (Cl, NH₃) 548(MH⁺). ¹H NMR (CD₃OD): (partial) δ 8.28 (br d, 1H), 7.32 (m, 5H), 7.18(m, 4H), 6.84 (m, 1H), 5.31 (m, 1H), 4.60 (m, 3H), 3.70 (m, 3H),3.18-2.92 (m, 3H), 2.68 (s, 3H), 1.57 (m, 6H), 1.13 (s, 9H).

EXAMPLE 12

[0378]2-Amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramideDihydrochloride

[0379] A. 4-Oxo-3-(R,S)-pyridin-2-ylmethyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl Ester 3-methyl Ester

[0380] To a solution of 2.00 g (7.8 mmol) of 3A in 32 mL of THF wasadded 468 mg (11.7 mmol) of sodium hydride (60% oil dispersion) at about0° C. and the mixture was stirred for about 30 min. A solution of 762 mg(6.0 mmol) 2-picolyl chloride in 5 mL of THF was added to the stirringsolution over about 5 min., followed by the addition of 432 mg (2.6mmol) of potassium iodide. The ice bath was removed and the mixture washeated for about 17 h at reflux. The mixture was diluted with ethylacetate and washed once with water and once with brine, dried overMgSO₄, and concentrated. The residue was purified by silica gelchromatography using (6:4 v/v ether:hexane) followed by (6:4 v/v ethylacetate:hexane) to give 1.2 g of 12A. MS (Cl, NH₃) 349 (MH⁺).

[0381] B.2-Methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-CarboxylicAcid tert-butyl Ester

[0382] A mixture of 1.20 g (3.45 mmol) of 12A and 159 mg (3.45 mmol) ofmethylhydrazine in 20 mL of ethanol was heated at reflux for about 6.5h. The mixture was concentrated and the residue was dissolved in 25 mLtoluene and heated at reflux for about 17 h. The mixture wasconcentrated and the residue was purified by silica gel chromatography(65:35 v/v ethyl acetate:hexane) to give 450 mg of 12B. MS (Cl, NH₃) 345(MH⁺).

[0383] C.2-Methyl-3a-(R,S)-pyridin-2-ylmethyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-oneDihydrochloride

[0384] A mixture of 450 mg (1.30 mmol) of 12B in 2 mL of 4M HCl/dioxanewas stirred at room temperature for about 4.5 h. The mixture wasconcentrated to give 450 mg of 12C. MS (Cl, NH₃) 245 (MH⁺).

[0385] D.{1-[1-(1-(R)-H-Indol-3-ylmethyl)-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0386] According to General Procedure A, 108 mg (0.31 mmol) of 12C and122 mg (0.31 mmol) of 2C were coupled and the residue was purified bysilica gel chromatography (95:5 v/v ethyl acetate:methanol) to give 118mg of 12D. MS (Cl, NH₃) 616 (MH⁺).

[0387] E.2-Amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidedihydrochloride

[0388] A mixture of 110 mg (0.18 mmol) of 12D in 1 mL of 4M HCl/dioxanewas stirred at room temperature for 17 h. The mixture was concentratedto give 51 mg of 12E. MS (Cl, NH₃) 516 (MH⁺). ¹HNMR (CD₃OD): (partial) δ8.91-8.52 (m, 2H), 8.04 (m, 2H), 7.76-7.50 (m, 3H), 6.82 (m, 1H), 4.62(m, 1H), 3.36 (s, 3H), 1.63 (s, 6H).

EXAMPLE 13

[0389]2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3.3a.4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramideDihydrochloride

[0390] A.{1-[1-(R)-Benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0391] According to General Procedure A, 86 mg (0.27 mmol) of 12C and103 mg (0.27 mmol) of 1E were coupled and the residue was purified bysilica gel chromatography (95:5 v/v ethyl acetate:hexane) to give 82 mgof 13A.

[0392] B.2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramideDihydrochloride

[0393] A mixture of 75 mg (0.12 mmol) of 13A in 1 mL of 4M HCl/dioxanewas stirred at room temperature for about 17 h. The mixture wasconcentrated to give 80 mg of 13B. MS (Cl, NH₃) 507 (MH⁺). ¹HNMR(CD₃OD): (partial) δ 8.78 (m, 1H), 8.46 (m, 1H), 8.13-7.82 (m, 2H), 7.32(m, 5H), 4.57 (m, 3H), 3.96 (m, 1H), 3.82 (m, 2H), 1.63 (m, 6H).

EXAMPLE 14

[0394]2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(benzyloxymethyl)-2-oxo-ethyl]-Isobutyramide

[0395] A. 4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl Ester3-methyl Ester

[0396] To a mixture of 100.0 g (516.4 mmol) of4-oxo-piperidine-3-carboxylic acid methyl ester and 63 g (516.4 mmol) of4,4-dimethylaminopyridine in 1 L of methylene chloride at about 0° C.was added a solution of 113.0 g (516.4 mmol) of di-tert-butyldicarbonatein 100 mL of methylene chloride over about 90 min. The mixture wasslowly warmed to room temperature and then stirred for about 19 h. Themixture was washed three times each with 10% aqueous HCl, saturatedaqueous sodium bicarbonate solution and brine, dried over MgSO₄ andconcentrated to give 130.5 g of 14A as an amorphous solid. ¹HNMR(CDCl₃): δ 4.03 (br, 2H); 3.74 (s, 3H), 3.56 (t, 2H), 2.36 (t, 2H), 1.42(s, 9H).

[0397] B. 3-(R)-Benzyl-4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl Ester 3-methyl Ester

[0398] To a stirred suspension of 11.7 g (293 mmol) of sodium hydride(60% oil dispersion washed twice with 100 mL of hexane) in 100 mL of DMFwas added a solution of 65.4 g (254 mmol) of 14A in 150 mL of DMF atabout 0° C. over about 45 min. The ice bath was removed and the mixturewas stirred at room temperature for about 45 min. The mixture wasrecooled to about 0° C. and 35.2 mL (296 mmol) of benzylbromide in 200mL of DMF was added dropwise to the stirring solution and the mixturewas stirred for about 23 h at room temperature. To the solution wascarefully added 550 mL of water and the mixture was stirred for about 30min. The mixture was extracted three times with ethyl acetate and thecombined organic extracts were washed five times with water, once withbrine, dried over MgSO₄ and concentrated to give 98 g of a yellow oil.The oil was crystallized from hexane to give 71 g of 14B as a whitesolid. MS (Cl, NH₃) 348 (MH⁺). ¹HNMR (CDCl₃): (partial) δ 7.23 (m, 3H),7.13 (m, 2H), 4.58 (br m, 1H), 4.18 (br, 1H), 3.63 (s, 3H), 3.28-2.96(m, 4H), 2.72 (m, 1H), 2.43 (m, 1H), 1.44 (s, 9H).

[0399] C.3a-(R)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicAcid tert-butyl Ester

[0400] A mixture of 47.0 g (135 mmol) of 14B, 38.9 g (270 mmol) ofmethylhydrazine sulfate and 44.3 g (540 mmol) of sodium acetate in 900mL of ethanol was heated at reflux for about 17 h under nitrogen. Themixture was concentrated and the residue was dissolved in ethyl acetateand washed three times with water and once with brine, dried over MgSO₄and concentrated to give a yellow oil. The oil was stirred in 750 mL ofhexane for about 3 h to give 41.17 g of 14C as a white solid. MS (Cl,NH₃) 344 (MH⁺). ¹HNMR (CDCl₃): (partial) δ 7.19 (m, 3H), 7.05 (m, 2H),4.61 (br m, 2H), 3.24 (m, 1H), 3.09 (s, 3H), 3.01 (m, 1H), 2.62 (m, 4H),1.52 (s, 9H).

[0401] D.3a-(R,S)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-oneHydrochloride

[0402] Anhydrous HCl was bubbled through a solution of 24.55 g (71.5mmol) of 14C in 800 mL of diethyl ether at about 0° C. for about 12 min.The mixture was stirred for about 3 h, during which time a whiteprecipitate formed. The precipitated solid was collected by filtrationand to give 19.2 g of 14D. MS (Cl, NH₃) 244 (MH⁺). ¹HNMR (CD₃OD):(partial) δ 7.25 (m, 3H), 7.05 (m, 2H), 3.77 (m, 2H), 3.51 (d, 1H), 3.25(m, 1H), 3.17 (m, 3H), 3.03 (s, 3H), 2.81 (m, 1H).

[0403] E. 2-tert-Butoxycarbonylamino-2-methyl-prorionic acid2,5-dioxo-pyrrolidin-1-yl Ester

[0404] To a stirring solution of 100.0 g (492 mmol) ofBoc-a-methylalanine and 94.0 g (492 mmol) of EDC in 2 L of methylenechloride at about 0° C. was added 56.63 g (492 mmol) ofN-hydroxysuccinimide in portions and the reaction was then allowed towarm to room temperature. The mixture was stirred for about 24 h andwashed twice each with saturated aqueous sodium bicarbonate solution andbrine, dried over Na₂SO₄ and concentrated to give 124.0 g of 14E as awhite solid. ¹HNMR (CDCl₃): δ 4.96 (br, 1H), 2.82 (s, 4H), 1.66 (s, 6H),1.48 (s, 9H).

[0405] F.3-(R)-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicAcid

[0406] A mixture of 50.5 g (168 mmol) of 14E, 33.5 g (168 mmol) ofO-benzyl-D-serine, and 51.05 g (505 mmol) of triethylamine in 400 mL ofdioxane and 100 mL of water was heated at about 45° C. for about 16 h.The mixture was diluted with ethyl acetate and acidified to pH 2 withacetic acid. The layers were separated and the organic phase was washedwith brine, dried over Na₂SO₄ and concentrated to give 650 g of 14F as awhite solid. ¹ HNMR (CD₃OD): (partial) δ 7.55 (d, 1H), 7.29 (m, 5H),4.52 (m, 1H), 4.48 (s, 2H), 3.84 (d of d, 1H), 3.69 (d of d, 1H), 1.42(s, 6H), 1.38 (s, 9H).

[0407] G.3a-(R)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-oneL-tartrate

[0408] To a mixture of 5.00 g (20.6 mmol) of the free base of 14D and3.09 g (20.6 mmol) of L-tartaric acid in 80 mL of acetone and 3.2 mL ofwater was heated under nitrogen at about 70° C. for about 70 h, duringwhich time the reaction mixture became a thick suspension and anadditional 20 mL of acetone was added. The reaction mixture was cooledslowly to room temperature and then filtered. The solid that wascollected was washed with acetone and dried under vacuum to give 7.03 gof 14G as a white solid.

[0409] H.3a-(R)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

[0410] To a suspension of 5.00 g (12.7 mmol) of 14G in 80 mL ofmethylene chloride at about 0° C. was added 1.72 mL (25.4 mmol) ofammonium hydroxide and the mixture was stirred for about 15 min. Thecold solution was filtered and used immediately in the next step.

[0411] I.{1-[2-(3a-(R)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(benzyloxymethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0412] A mixture of 4.83 g (12.7 mmol) of 14F, the solution from 14H,2.60 g (19.1 mmol) of HOAT, and 2.45 g (12.8 mmol) of EDC was stirred atabout 0° C. under nitrogen for about 1 h and then warmed to roomtemperature and stirred for about 16 h. The mixture was filtered and thefiltrate was washed with saturated aqueous sodium bicarbonate and water,dried over MgSO₄ and concentrated to give 7.35 g of 14I as a whitesolid.

[0413] J.2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(benzyloxymethyl)-2-oxo-ethyl]-isobutyramide

[0414] To 755 mg (1.25 mmol) of 141 in 7 mL of methylene chloride atabout 0° C. was added 3.5 mL of cold trifluoroacetic acid and themixture was stirred for about 1 h at about 0° C. The mixture was allowedto warm to room temperature and stirred for about 2 h. The mixture wasconcentrated and co-evaporated twice with toluene. The residue wasdissolved in chloroform and washed twice with saturated aqueous sodiumbicarbonate and once each with water and brine. The mixture was driedover MgSO₄ and concentrated to give 594 mg of 14J as an oil.

EXAMPLE 15

[0415]2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramideHydrochloride

[0416] A.2-Methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicAcid tert-butyl Ester

[0417] A mixture of 3.00 g (11.66 mmol) of 3A and 537 mg (11.66 mmol) ofmethylhydrazine in 100 mL of ethanol was heated at reflux for about 17h. The mixture was concentrated and the residue was dissolved in 100 mLtoluene and heated at reflux for about 17 h. The mixture was dilutedwith ethyl acetate, and washed twice with brine, dried over MgSO₄ andconcentrated. The residue was purified by silica gel chromatographyusing an elution gradient of 100% ethyl acetate to 5% methanol inmethylene chloride to give 2.28 g of 15A as a white solid. ¹HNMR(CD₃OD): δ 4.20 (s, 2H), 3.67 (t, 2H), 3.43 (s, 3H), 2.58 (t, 2H), 1.48(s, 9H).

[0418] B. 2-Methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-oneHydrochloride

[0419] To 510 mg (2.01 mmol) of 15A in 30 mL of ethanol was added 10 mLof concentrated HCl and the mixture was stirred at room temperature forabout 35 min. The mixture was concentrated and the residue wascrystallized from methanol/ethyl acetate to give 425 mg of 15B as ayellow solid. ¹HNMR (CD₃OD): δ 4.27 (S, 2H), 3.71 (S, 3H), 3.56 (T, 2H),3.05 (T, 2H).

[0420] C.{1-[1-(R)-Benzyloxymethyl-2-(2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0421] According to the method outlined in General Procedure A, 100 mg(0.53 mmol) of 15B and 202 mg (0.53 mmol) of 1E were coupled and theresidue was purified by silica gel chromatography (95:5 v/v methylenechloride:methanol) to give 54 mg of 15C as a white solid. MS (Cl, NH₃)516 (MH⁺).

[0422] D.2-Amino-N-[1-R-benzyloxymethyl-2-(2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramideHydrochloride

[0423] To 54 mg (0.10 mmol) of 15C in 30 mL of ethanol was added 10 mLof concentrated HCl and the mixture was stirred at room temperature forabout 40 min. The mixture was concentrated and the residue wasprecipitated from methanol/ethyl acetate to give 50 mg of 15D. MS (Cl,NH₃) 416 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.28 (m, 5H), 5.18 (m 1H),4.69-4.38 (m, 4H), 3.88 (m, 1H), 3.73 (m, 2H), 3.68 (s, 2H), 3.61 (m,1H), 2.67 (m, 1H), 1.57 (s, 6H).

EXAMPLE 16

[0424]2-Amino-N-[2-(2-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramideHydrochloride

[0425] A.2-Benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicAcid tert-butyl Ester

[0426] A mixture of 800 mg (3.11 mmol) of 3A and 495 mg (3.11 mmol) ofbenzyl-hydrazine dihydrochloride in 15 mL of ethanol was heated atreflux for about 17 h. The mixture was concentrated and the residue wasdissolved in 100 mL toluene and heated at reflux for about 48 h. Themixture was diluted with ethyl acetate, and washed twice with brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography using an elution gradient of 100% ethyl acetate to 5%methanol in methylene chloride to give 530 mg of 16A as a tan solid. MS(Cl, NH₃) 330 (MH⁺).

[0427] B. 2-Benzyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-oneHydrochloride

[0428] To 411 mg (1.24 mmol) of 16A in 30 mL of ethanol was added 10 mLof concentrated HCl and the mixture was stirred at room temperature forabout 30 min. The mixture was concentrated and the residue wascrystallized from methanol/ethyl acetate to give 353 mg of 16B as ayellow solid. MS (Cl, NH₃) 230 (MH⁺). ¹ HNMR (CD₃OD): δ 7.26-7.40 (m,5H), 5.22 (s, 2H), 4.12 (s, 2H), 3.53 (t, 2H), 3.00 (t, 2H).

[0429] C.(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-Propionylamino)-3-(1H-indol-3-yl)-propionicAcid

[0430] To a stirring solution of 30.6 g (0.15 mol) of D-tryptophan, 30.4g (0.30 mol) of N-methylmorpholine in 450 mL of (4:1) dioxane:water, wasadded 45.0 g (0.15 mol) of 14E and the mixture was stirred for about 72h. Excess dioxane was removed by evaporation and water and ethyl acetatewere added to the mixture. The pH of the solution was adjusted to 3 withconcentrated HCl and the layers were separated. The organic layer waswashed with water and brine, dried over MgSO₄ and concentrated. Theresidue was crystallized from ethyl acetate/hexanes to give 37.0 g of anoff-white solid.

[0431] D.{1-[2-(2-Benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-butyl Ester

[0432] According to the method outlined in General Procedure A, 100 mg(0.38 mmol) of 16B and 202 mg (0.53 mmol) of 16C were coupled and theresidue was purified by silica gel chromatography (95:5 v/v methylenechloride:methanol) to give 45 mg of 16D as a white solid. MS (Cl, NH₃)601 (MH⁺).

[0433] E.2-Amino-N-[2-(2-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4.3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

[0434] To 45 mg (0.07 mmol) of 16D in 60 mL of ethanol was added 20 mLof concentrated HCl and the mixture was stirred at room temperature for35 min. The mixture was concentrated and the residue was precipitatedfrom methanol/ethyl acetate to give 30 mg of 16E. ¹HNMR (CD₃OD):(partial) δ 7.40 (m, 4H), 7.25 (m, 3H), 7.11 (m, 2H), 6.96 (m, 2H), 6.81(m, 1H), 5.38-4.93 (m, 3H), 4.46 (m, 1H), 4.22 (m, 1H), 3.96 (m, 1H),3.69 (m, 1H), 3.18 (m, 1H), 2.28 (m, 1H), 1.57 (m, 6H), 1.38 (m, 1H).

EXAMPLE 17

[0435]2-Amino-N-[1-benzyloxymethyl-2-(2,3a-dimethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramideHydrochloride

[0436] A. 3-Methyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-(R,S)-methyl Ester

[0437] To a solution of 2.00 g (7.77 mmol) 3A in 30 mL of DMF was added308 mg (7.77 mmol) of sodium hydride (60% oil dispersion) and themixture was stirred at room temperature for about 25 min. To thestirring solution was added 0.50 mL (7.77 mmol) of methyl iodide and themixture was stirred for about 17 h at room temperature. The mixture wasdiluted with ethyl acetate and washed once with water and four timeswith brine, dried over MgSO₄, and concentrated. The residue was purifiedby silica gel chromatography (7:3 v/v hexane:ethyl acetate) to give 1.75g of 17A as a clear oil. MS (Cl, NH₃) 272 (MH⁺).

[0438] B.2,3a-(R,S)-Dimethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4.3-c]pyridine-5-carboxylicacid tert-butyl ester

[0439] A mixture of 1.62 g (9.50 mmol) of 17A and 435 mg (9.50 mmol) ofmethylhydrazine in 30 mL of ethanol was heated at reflux for about 4 h.The mixture was concentrated and the residue was dissolved in 50 mLtoluene and heated at reflux for about 14 h. The mixture was dilutedwith ethyl acetate, and washed twice with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography (7:3v/v hexane:ethyl acetate) to give 1.00 g of 17B as a white solid. MS(Cl, NH₃) 268 (MH⁺).

[0440] C.2,3a-(R,S)-Dimethyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onehydrochloride

[0441] To 1.00 g (3.74 mmol) of 17B in 40 mL of ethanol was added 8 mLof concentrated HCl and the mixture was stirred at room temperature forabout 35 min. The mixture was concentrated and the residue wascrystallized from methanol/ethyl acetate to give 850 mg of 17C as awhite solid. MS (Cl, NH₃) 168 (MH⁺).

[0442] D.{1-[1-(R)-Benzyloxymethyl-2-(2,3a-(R,S)-dimethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0443] According to the method outlined in General Procedure A, 150 mg(0.74 mmol) of 17C and 514 mg (1.35 mmol) of 1E were coupled and theresidue was purified by silica gel chromatography (85:15 v/vhexane:ethyl acetate) to give 185 mg of 17D as a white solid.

[0444] E.2-Amino-N-[1-(R)-benzyloxymethyl-2-(2,3a-(R,S)-dimethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidehydrochloride

[0445] To 173 mg (0.33 mmol) of 17B in 40 mL of ethanol was added 15 mLof concentrated HCl and the mixture was stirred at room temperature forabout 1 h. The mixture was concentrated and the residue was diluted withchloroform and washed with saturated aqueous sodium bicarbonate andbrine, dried over Na₂SO₄ and the residue was purified by silica gelchromatography using an elution gradient of 100% ethyl acetate to 10%diethylamine in ethyl acetate. The residue was dissolved in ethanol andacidified with aqueous HCl. The mixture was concentrated and the residuewas crystallized from methanol/ethyl acetate to give 65 mg of 17E as awhite solid. MS (Cl, NH₃) 502 (MH⁺). ¹HNMR (CD₃OD): (partial) δ7.32 (m,5 H), 5.14 (m, 1 H), 4.53 (m, 3 H), 3.71 (m, 3 H), 2.97 (m, 1 H), 2.83(m, 1 H), 2.57 (m, 1 H), 1.98 (m, 2 H), 1.61 (m, 6 H), 1.38 (s, 3 H).

EXAMPLE 18

[0446]2-Amino-N-[2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrocloride and

[0447]2-Amino-N-[2-(3a-(S)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

[0448] A. 3-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester

[0449] To 200 mg (0.58 mmol) of 3B at about 0° C. was added 5 mL of coldtrifluoroacetic acid and the mixture was stirred for about 1 h. Themixture was concentrated and the residue was co-evaporated with ethylacetate and hexane. To the residue was added 2N NaOH to make it basicand the mixture was extracted with chloroform. The combined organicextracts were dried over MgSO₄ and concentrated to give 18A inquantitative yield.

[0450] B.3-(R,S)-Benzyl-1-[3-benzyloxy-2-(R)-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionyl]-4-oxo-piperidine-3-carboxylicacid methyl ester

[0451] According to the method outlined in General Procedure A, 1.77 g(7.16 mmol) of 18A and 3.04 g (8.0 mmol) of 14F were coupled to give amixture of diastereomers. The residue was purified by silica gelchromatography (7:3 v/v hexane:ethyl acetate) to give 820 mg of lesspolar 18B isomer 1 and 1.14 g more polar 18B isomer 2. MS (Cl, NH₃) 611(MH⁺) for both isomers.

[0452] C.{1-[2-(3a-(R,S)-Benzyl-3-oxo-2,3,3,a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0453] To a solution of 820 mg (1.32 mmol) of 18B isomer 1 in 13 mL ofethanol was added 342 mg (2.63 mmol) of hydrazine sulfate and 431 mg(5.26 mmol) of sodium acetate and the mixture was heated at reflux forabout 17 h. The mixture was concentrated and the residue was dilutedwith ethyl acetate and washed with saturated aqueous sodium bicarbonateand brine, dried over MgSO₄ and concentrated. The residue was purifiedby silica gel chromatography using an elution gradient of 75% ethylacetate in hexane to 100% ethyl acetate to give 550 mg of 18C isomer 1.

[0454] To a solution of 1.14 g (1.86 mmol) of 18B isomer 2 in 20 mL ofethanol was added 485 mg (3.73 mmol) of hydrazine sulfate and 613 mg(7.48 mmol) of sodium acetate and the mixture was heated at reflux forabout 17 h. The mixture was concentrated and the residue was dilutedwith ethyl acetate and washed with saturated aqueous sodium bicarbonateand brine, dried over MgSO₄ and concentrated. The residue was purifiedby silica gel chromatography (75:25 v/v ethyl acetate/hexane) to give710 mg of 18C isomer 2.

[0455] D.2-Amino-N-[2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

[0456] To 200 mg (0.34 mmol) of 18C isomer 1 in 12 mL of ethanol wasadded 6 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 2.5 h. The mixture was concentrated andco-evaporated three times with ethanol to give 20 mg of 18D isomer 1. MS(Cl, NH₃) 492 (MH⁺). ¹HNMR (CD₃OD): (partialδ 8.42 (br d, 1 H), 7.35 (m,5 H), 7.18 (m, 5 H), 5.23 (m, 2 H), 4.91 (m, 1 H), 4.54 (m, 4 H), 3.80(m, 2 H), 3.63 (m, 1 H), 3.12 (m, 1 H), 3.07 (m, 3 H), 2.61 (m, 3 H),1.62 (m, 6 H), 1.39 (m, 1 H).

[0457] E.2-Amino-N-[2-(3a-(S)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochlorde

[0458] To 200 mg (0.34 mmol) of 18C isomer 2 in 20 mL of ethanol wasadded 10 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 2.5 h. The mixture was concentrated andco-evaporated three times with ethanol to give 30 mg of 18E isomer 2. MS(Cl, NH₃) 492 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 8.29 (br d, 1 H), 7.30(m, 5 H), 7.11 (m, 4 H), 6.88 (m, 1 H), 5.29 (m, 1 H), 4.92 (m, 1 H),4.62 (m, 3 H), 3.91-3.70 (m, 3 H), 3.22-2.95 (m, 3 H), 1.57 (m, 6 H),1.30 (m, 1 H), 0.89 (m, 1 H).

EXAMPLE 19

[0459]2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-thiazol-4-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidedihydrochloride

[0460] A. 4-Oxo-3-(R,S)-thiazol-4-ylmethyl-piperidine-1,3-dicarboxylicacid 1 -tert-butyl ester 3 -ethyl ester

[0461] To a solution of 300 mg (1.10 mmol) of 1A in 5 mL of THF at about20 C. was added 67 mg (1.66 mmol) of sodium hydride (60% oil dispersion)and the mixture was stirred for about 30 min. A solution of 204 mg (1.21mmol) of 4-chloromethylthiazole (Hsiao, C. N; Synth. Comm. 20, p. 3507(1990)) in 5 mL of THF was added to the cold solution, followed by 87 mg(0.53 mmol) of potassium iodide and the mixture was heated at reflux forabout 17 h. The mixture was diluted with water and extracted with ethylacetate. The combined organic extracts were dried over Na₂SO₄ andconcentrated and the residue was purified by silica gel chromatography(7:3 v/v hexane:ethyl acetate) to give 90 mg of the title compound. (MS(Cl, NH₃) 648 (MH⁺).

[0462]2-Methyl-3-oxo-3a-(R,S)-thiazol-4-ylmethyl-2,3,3a4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

[0463] To 90 mg (0.24 mmol) of 19A in 2ml or ethanol was added 11.2 mg(0.24 mmol) of methylhydrazine and the mixture was heated at refux forabout 17 h. An additional 33.6 mg (0.72 mmol) of methylhydrazine wasadded and the mixture was heated at reflux for about 7 h. The mixturewas concentrated and the residue was dissolved in 3 mL of toluene andheated at reflux for about 17 h. The mixture was concentrated and theresidue was purified by silica gel chromatography (6;4 v/v hexane: ethylacetate) to give 44 mg of 19B. MS (Cl, NH₃) 648 (MH⁺).

[0464] C.2-Methyl-3a-(R,S)-thiazol-4-ylmethyl-2,3a4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onedihydrochloride

[0465] A mixture of 44 mg (0.10 mmol) or 19B in 1 mL of 4M HCl indioxane was stirred at room temperature for avout 4h. The mixture wasconcentrated and co-evaporated with methylene chloride to give 40 mg of19C. MS (Cl, NH₃) 251 (MH⁺).

[0466] D.{1-[1-(R)-Benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-thiazol-4-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0467] According to the method outlined in General Procedure A, 40 mg(0.12 mmol) of 19C and 39 mg (0.12 mmol) of 14F were coupled and theresidue was purified by silica gel chromatography (9:1 v/v ethylacetate:hexane) to give 40 mg of 19D. MS (Cl NH₃) 613 (MH⁺).

[0468] E.2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-thiazol-4-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidedihydrochloride

[0469] A mixture of 40 mg (0.06 mmol) of 19D in 1 mL of 4M HCl indioxane was stirred at room temperature for about 5 h. The mixture wasconcentrated and co-evaporated with methylene chloride to give 40 mg of19E. MS (Cl, NH₃) 513 (MH⁺).

EXAMPLE 20

[0470]2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-(benzylosymethyl)-2-oxo-ethyl]-isobutyramideL-tartaric acid salt

[0471] To 4.6 g of the title compound of Example 14 in 20 mL ofmethanol, a solution of 1.36 g of L-tartaric acid in 20 mL of methanolwas added at about 0° C. The misture was warmed to room temperature,stirred for about 40 min. and concentrated in vacuo. The residure wasdiluted with 220 mL of ethyl acetate, heated at reflux for about 1.5 h,then stirred about 72° C. for about 18 h. The mixture was cooled to roomtemperature, and filtered to give 5.78 g of the title compound as acolorless crystaline solid.

EXAMPLE 21

[0472] 3-Benzyl-3-methoxycarbonylmethyl-4-oxo-piperidine-1-carboxylicacid tert-butyl ester A. 3-Benzyl-4-oxo-piperidine-1-carboxylic acidtert-butyl ester

[0473] A mixture of the β-ketoester (4480 mg, 12,9 mmol) and LiCl (1100mg, 25.8 mmol) was heated in DMF (2.0 mL) at about 120° C. for about 17h. The reaction mixture was cooled to room temperature and extractedwith EtOAc (3×100 mL). The combined extracts were dried and concentratedin vacuo. The crude product was chromatographed on SiO₂ using 20% ethylacetate/hexanes to give 1320 mg of the desired product as a yellow oil.¹H NMR (250 MHz, CDCl₃): d: 7.4 (m,5H), 4,2 (m,1H), 3.4 (m, 1 H), 3.05(dd, 1 H), 2.55 (m, 4H), 1.5 (s,9H); MS (APCl): 190 (M+1−BOC).

[0474] B. 3-Benzyl-3-methoxycarbonylmethyl-4-oxo-poperidine-1-carboxylicacid tert-butyl ester

[0475] A solution of the preduct from Step A of Example 21 above (1320mg, 4.56 mmol), pyrrolidine (972 mg, 13 mmol) and p-toluenesulfonic acid(33 mg) in benzene (30 mL) was refuxed through 3a molecular cieves forabout 17 h. The reaction mixture was cooled to room temperature andconcertrated in vacuo. The residue was dissolved in benzene (10 mL) andcooled to about 0° C. Methyl bromoacetate (1530 mg, 10 mmol) was addeddropwise. The reaction mixture was slowly allowed to warm to roomtemperature and then was heated under reflux for about 17 h at whichpoint H₂O (5 mL) was added. After refuxing for about another 2 h, thereaction mixture was cooled to room temperature and extracted with EtOAc(3×100 mL). The combined organic extracts were dried and concentrated invacuo. The crude residue was chromatographed on SiO₂-gel using 15% ethylacetate/hexanes to give 280 mg of product. ¹H NMR (250 MHz, CDCl₃): d7.35 (m, 5 H), 4.5 (m, 1H), 3.8 (s, 3H), 3,4 (dd, 1 H), 3.1 (m, 1 H),2.85 (m, 4H), 2.6 (m, 1 H), 2.4 (m, 1 H), 1.5 (s, 9 H); MS (APCI): 362(M+1).

EXAMPLE 22

[0476] 6-Oxo-1-phenyl-cyclohexane-1,3-dicarboxylic acid 3-tert-butylester 1-methyl ester

[0477] A soution of diphenylmercury (890 mg, 2.5 mmol) in CHCl₃ (4 mL)under N₂ was heated to about 40° C. Lead tetraacetate (1100 mg, 2.5mmol) was added in small potions and the greenish yellow solution wasstirred at about 40° C. for about 0.5 h. The β-ketoester (520 mg, 2.0mmol) was then added, followed by pyridine (0.2 mL, 2.5 mmol). Afterabout 5 h at about 40° C., the ractio mixture was concentrated in vacuoand the residue was dissovled in ether (100 mL) and filtered. Thefiltrate was washed with 3N H₂SO₄ (3×), dried and concentrated to give616 mg of a yellow solid. Flash chromatography over SiO₂-gel using 25%ethyl acetate/hexanes provided 368 mg of the desired product. ¹H NMR(400 MHz, CDCl₃): d 7.15 (, 5 H), 3.7 (s, 5 H), 1.5 (s, 9H); MS (APCI):334 (M+1)

EXAMPLE 23

[0478] (D)-2-Amino-3-(2,4-dichloro-benzyloxy)-propionic acidhydrochloride

[0479] A. (D)-2-tert-Butoxycarbonylamino-3-(2,4-dichloro-benzyloxy)-propionic acid

[0480] To a stirred solution of Boc-D-serine (8.2 g, 40 mmol) in DMF 975mL) at about 0° C. was added NaH (60% dispersion, 3,2 g, 80 mmol) overabout a 10 minute period. The reaction misture was stirred for about1.75 h at about 0° C., then about 0.25 h at room temperature. Aftercooling to about 0° C., a solution of 2,4-dichlorotoluene (5.56 mL, 40mmol) in DMF (5mL) was added dropwise. The reaction mixture was allowedto warm to about 23° C. and was stirred for about 17 h, then waspartitioned between di-isopropylether and 10% HCl. The aqueous solutionwas extracted with di-isopropyl ether (2×). The combined extracts werewashed wth sturated aqueoud brine, dried and concentrated to gove 14.75g of crude product which was used without further purification. ¹H NMR(400 MHz, CDCl₃): d 7.6-7.2 (m, 3 H), 5.4 (d, 1 H), 4,6 (s, 2 H), 4.0(d, 1 H), 3.8 (dd, 2 H), 1.1 (s, 9H); MS (APCI): 264,266 (M+1,M+2).

[0481] B. (D)-2-Amino-3-(2,4-dichloro-benzyloxy)-propionic acidhydrochloride

[0482] The product from step A of Example 23 above (14.7 g, 40 mmol) wasstirred in 4 M HCl/dioxane (100 mL) for about 17 h. The reaction mixturewas concentrated in vacuo to give 12 g of pale yellow solid (100%). MS(APCI):265 (M+1).

EXAMPLE 24

[0483] Example 24 having the formula shown below,

[0484] wherein R¹ is—CH₂-phenyl and R² is methyl, was synthesized in ananalogous manner to the procedured described in Examples 3C to 3F usingthe title compound of Example 21 as starting material. Both the R,R andS,R diastereomers (* indicates the other stereoisomer center at the C-3carbon of the above structure) were isolated. Mass spec. (M+1)=520; MSmethod=particle bombardment.

EXAMPLE 25 and 26

[0485] Examples 25 and 26 having the formula shown below,

[0486] wherein for both examples 25 and 26 R¹ is phenyl and R² ismethyl, where example 25 is the R,R isomer and example 26 is the S,Risomer. Examples 25 and 26 were synthesized in an analogous manner tothe procedures described in Examples 3C to 3F using the title compoundof Example 22 as starting material followed by chromatographicseparation of the two separate isomers. Mass spec. of each example(M+1)=493, MS method=particle bombardment.

EXAMPLES 27-159

[0487] Examples 27 to 159 listed in the table below, were preparedaccording to the scheme illustrated below by coupling the appropriatelysubstituted pyrazalone-piperidine of formula I (in the below scheme)with the (D)-ObnSer derivative II (in the below scheme) in an analogousmanner to the procedures described in Examples 3E and 3F.

[0488] The pyrazalone-piperidines of formula I were prepared analogouslyaccording to the procedures described in Examples 3B and 3C startingwith the appropriate alkylating agent and alkylhydrazine; the (D)-ObnSerderivatives (II) were prepared in three steps analogously to theprocedures described in Example 23A, Example 23B and Example 5F.

R¹ = —CH₂—A¹ Ex. # Isomer R² A¹ Ar MS MS Method 27 d1 H 2-pyridyl phenyl493 PB 28 d1 H 4-thiazolyl phenyl 499 PB 29 d2 H 4-thiazolyl phenyl 499PB 30 d1 H 5-thiazolyl phenyl 499 APCI 31 d1 Me phenyl 2,4-di-Cl—Ph574.5 APCI 32 d1 Me phenyl 2,4-di-F—Ph 542 PB 33 d1 Me phenyl[2,3-O—CH₂O]Phenyl 550.2 PB 34 d1 Me phenyl 2-CF₃—Ph 575 PB 35 d1 Mephenyl 2-Me—Ph 520 PB 36 d1 Me phenyl 2-pyridyl 507 PB 37 d1 Me phenyl3,4-di-F—Ph 542 PB 38 d1,2 Me phenyl 3,5-di-CF₃—Ph 642 PB 39 d1 Mephenyl 3,5-di-Cl—Ph 576 APCI 40 d2 Me phenyl 3-CF₃—Ph 575 APCI 41 d1 Mephenyl 3-Cl—Ph 540 APCI 42 d1 Me phenyl 3-Cl-thiophene 546,548 APCI 43d1 Me phenyl 3-F-4-Cl—Ph 560 APCI 44 d1 Me phenyl 3-Me—Ph 520 PB 45 d1Me phenyl 4-Cl—Ph 540 PB 46 d1 Me phenyl 4-pyridyl 507 PB 47 d1 Mephenyl 4-thiazolyl 513 PB 48 d1 Me phenyl 5-thiazolyl 513 APCI 49 d1,2Me phenyl benzisoxazolyl 547 PB 50 d1 Me phenyl 4-pyrimidinyl 508 PB 51d1,2 Me 4-Ph-Ph 4-thiazolyl 589 APCI 52 d1,2 Me 4-Ph-Ph 2-pyridyl 583APCI 53 d1 Me 4-F—Ph phenyl 524 PB 54 d2 Me 4-F—Ph phenyl 524 PB 55 d1Me 4-F—Ph 3-Cl—Ph 558 PB 56 d2 Me 4-F—Ph 3-Cl—Ph 558 PB 57 d1 Me 4-F—Ph3,4-di-F—Ph 560 APCI 58 d2 Me 4-F—Ph 3,4-di-F—Ph 560 APCI 59 d1,2 Me4-F—Ph 2-pyridyl 525 APCI 60 d1,2 Me 4-F—Ph 2-CF₃—Ph 592 APCI 61 d1 Me4-CF₃—Ph 4-Cl—Ph 609 APCI 62 d1,2 Me 4-CF₃—Ph 4-Cl—Ph 609 APCI 63 d1,2Me 3-pyridyl phenyl 508 PB 64 d1 Me phenyl 3-pyridyl 508 PB 65 d1 Me2-quinolinyl phenyl 594 PB 66 d2 Me 2-quinolinyl phenyl 594 PB 67 d1 Me2-pyridyl phenyl 506 PB 68 d2 Me 2-pyridyl phenyl 506 PB 69 d1,2 Me2-pyridyl 3-F-4-Cl—Ph 559,561 APCI 70 d1 Me 2-pyridyl 3-Cl-thiophene547,549 APCI 71 d1 Me 2-pyridyl 3-CF₃—Ph 575 PB 72 d1,2 Me 2,4-di-F—Ph3,4-di-F—Ph 579 APCI 73 d1,2 Me 2,4-di-F—Ph 2-pyridyl 544 PB 74 d1 Me4-thiazolyl phenyl 513 APCI 75 d2 Me 4-thiazolyl phenyl 513 PB 76 d1 Me5-thiazolyl phenyl 513 PB 77 d1 Et 2-pyridyl phenyl 521 PB 78 d1,2 Etphenyl 4-thiazolyl 541 APCI 79 d1 Et phenyl 3,5-di-CF₃—Ph 656 PB 80 d1,2Et phenyl 3,4-di-F—Ph 556 PB 81 d1 Et 2,4-di-F—Ph 2,4-di-F—Ph 593 APCI82 d2 Et 2,4-di-F—Ph 2,4-di-F—Ph 593 APCI 83 d1 Et 2,4-di-F—Ph 2-CF₃—Ph625 APCI 84 d2 Et 2,4-di-F—Ph 2-CF₃—Ph 625 APCI 85 d1 Et 2,4-di-F—Ph3,4-di-F—Ph 593 APCI 86 d2 Et 2,4-di-F—Ph 3,4-di-F—Ph 593 APCI 87 d1 Et2-pyridyl 3,4-di-F—Ph 607 PB 88 d2 Et 2-pyridyl 3,4-di-F—Ph 607 PB 89 d1Et 4-CF₃—Ph 2,4-di-F—Ph 625 APCI 90 d2 Et 4-CF₃—Ph 2,4-di-F—Ph 625 APCI91 d1 Et 4-CF₃—Ph 3-Cl—Ph 623 APCI 92 d1 Et 4-CF₃—Ph 4-Cl—Ph 623 APCI 93d2 Et 4-CF₃—Ph 4-Cl—Ph 623 APCI 94 d1 Et 4-CH₃—Ph 3-Cl—Ph 568 APCI 95 d2Et 4-CH₃—Ph 3-Cl—Ph 568 APCI 96 d1 Et 4-Cl—Ph 3,4-di-F—Ph 590 PB 97 d2Et 4-Cl—Ph 3,4-di-F—Ph 590 PB 98 d1 Et 4-Cl—Ph 3-5-di-Cl—Ph 622 PB 99 d2Et 4-Cl—Ph 3-5-di-Cl—Ph 622 PB 100 d1 Et 4-Cl—Ph 3-Cl—Ph 589 PB 101 d2Et 4-Cl—Ph 3-Cl—Ph 589 PB 102 d1 Et 4-F—Ph 3,4-di-F—Ph 574 PB 103 d2 Et4-F—Ph 3,4-di-F—Ph 574 PB 104 d1 Et 4-F—Ph 3-Cl—Ph 572 APCI 105 d2 Et4-F—Ph 3-Cl—Ph 572 APCI 106 d1,2 Et 4-Me-Ph 2-CF₃—Ph 602 APCI 107 d1,2Et 4-Me-Ph 3,4-di-F—Ph 570 APCI 108 d1,2 CF₃CH₂ phenyl 4-thiazolyl 595APCI 109 d1 CF₃CH₂ phenyl 3-CF₃—Ph 642.3 APCI 110 d1 CF₃CH₂ phenyl3,5-di-Cl—Ph 643 APCI 111 d2 CF₃CH₂ phenyl 3,5-di-Cl—Ph 644 APCI 112 d1CF₃CH₂ phenyl 3,4-di-F—Ph 610.2 APCI 113 d2 CF₃CH₂ phenyl 3,4-di-F—Ph610.2 APCI 114 d1 CF₃CH₂ phenyl 3,5-di-Cl—Ph 643 APCI 115 d2 CF₃CH₂phenyl 3,5-di-Cl—Ph 644 APCI 116 d1 CF₃CH₂ phenyl 3-CF₃—Ph 642.3 APCI117 d1 CF₃CH₂ phenyl 3,4-di-F—Ph 610.2 APCI 118 d2 CF₃CH₂ phenyl3,4-di-F—Ph 610.2 APCI 119 d1,2 CF₃CH₂ phenyl 4-thiazolyl 595 APCI 120d1,2 CF₃CH₂ 2,4-di-Cl—Ph 2-pyridyl 643 APCI 121 d1,2 CF₃CH₂ 2,4-di-Cl—Ph4-thiazolyl 649 APCI 122 d1 CF₃CH₂ 2,4-F—Ph 2-CF₃—Ph 679 APCI 123 d2CF₃CH₂ 2,4-F—Ph 2-CF₃—Ph 679 APCI 124 d1 CF₃CH₂ 2,4-F—Ph 3,4-di-F—Ph 647APCI 125 d2 CF₃CH₂ 2,4-F—Ph 3,4-di-F—Ph 647 APCI 126 d1,2 CF₃CH₂2,4-F—Ph 4-thiazolyl 617 PB 127 d1 CF₃CH₂ 2-pyridyl 2,4-di-Cl—Ph 643APCI 128 d2 CF₃CH₂ 2-pyridyl 2,4-di-Cl—Ph 643 APCI 129 d1 CF₃CH₂2-pyridyl 2,4-di-F—Ph 611 PB 130 d2 CF₃CH₂ 2-pyridyl 2,4-di-F—Ph 611 PB131 d1 CF₃CH₂ 2-pyridyl 2-CF₃-4-F—Ph 661 APCI 132 d1 CF₃CH₂ 2-pyridyl2-CF₃—Ph 643 PB 133 d2 CF₃CH₂ 2-pyridyl 2-CF₃—Ph 643 PB 134 d1 CF₃CH₂2-pyridyl 3,4-di-F—Ph 611 PB 135 d2 CF₃CH₂ 2-pyridyl 3,4-di-F—Ph 611 PB136 d1 CF₃CH₂ 2-pyridyl 3,5-di-Cl—Ph 643 APCI 137 d1 CF₃CH₂ 2-pyridyl3-Cl—Ph 609 PB 138 d1 CF₃CH₂ 2-pyridyl 3-Cl-thiophene 615,617 APCI 139d1,2 CF₃CH₂ 2-pyridyl 3-F-4-Cl—Ph 627,629 APCI 140 d1 CF₃CH₂ 2-pyridyl3-OCF₃—Ph 659 APCI 141 d1 CF₃CH₂ 2-pyridyl 4-Cl—Ph 609 PB 142 d2 CF₃CH₂2-pyridyl 4-Cl—Ph 609 PB 143 d1,2 CF₃CH₂ 3-pyridyl 2,4-di-F—Ph 612 APCI144 d1,2 CF₃CH₂ 3-pyridyl 2-CF₃—Ph 644 APCI 145 d1,2 CF₃CH₂ 3-pyridyl4-Cl—Ph 610 APCI 146 d1 CF₃CH₂ 4-CH₃—Ph 3-Cl—Ph 622 APCI 147 d2 CF₃CH₂4-CH₃—Ph 3-Cl—Ph 622 APCI 148 d1 CF₃CH₂ 4-Cl—Ph 3,4-di-F—Ph 644 PB 149d2 CF₃CH₂ 4-Cl—Ph 3,4-di-F—Ph 644 PB 150 d1 CF₃CH₂ 4-Cl—Ph 3,5-di-Cl—Ph675 PB 151 d2 CF₃CH₂ 4-Cl—Ph 3,5-di-Cl—Ph 675 PB 152 d2 CF₃CH₂ 4-Cl—Ph3-Cl—Ph 642 PB 153 d1 CF₃CH₂ 4-Cl—Ph 3-Cl—Ph 642 PB 154 d1 CF₃CH₂ 4-F—Ph3,4-di-F—Ph 628 PB 155 d2 CF₃CH₂ 4-F—Ph 3,4-di-F—Ph 628 PB 156 d1 CF₃CH₂4-F—Ph 3-Cl—Ph 626 PB 157 d2 CF₃CH₂ 4-F—Ph 3-Cl—Ph 626 PB 158 d1,2CF₃CH₂ 4-Me-Ph 2-CF₃—Ph 656 APCI 159 d1,2 CF₃CH₂ 4-Me-Ph 3,4-di-F—Ph 624APCI

[0489] Example 37: ¹H NMR (400 MHz, d4-MeOH): d 7.2 (m,5H), 5.2 (t,1H),4.6 (m, 3H), 3.8 (d, 2H), 3.1 (d,1H), 3.0 (s,3H), 2.6 (dd,2H), 1.6(s,6H).

[0490] Example 67 & 68: ¹H NMR (300 MHz, d4-MeOH): d 8.85 (s,1H), 8.6(t,1H), 8.1 (d, 1H), 8.0 (t,1H), 7.35 (s,5H), 5.15 (s,1H), 4.6 (bs, 3H),3.85 (m,2H), 3.65 (m,2H), 3.2 (s,3H), 2.75 (m,2H), 1.65 (s,6H).

[0491] Example 128: ¹H NMR (400 MHz, d4-MeOH): d 8.8 (d,1H), 8.6 (s,1H),8.5 (t,1H), 7.68 (t,1H), 7.9 (d,1H), 7.45 (d,1H), 7.33 (d,1H), 5.2(s,1H), 4.6 (s,3H), 4.4 (m,1H), 4.2 (m,2H), 3.9 (m,4H), 3.5 (m), 3.2(m,2H), 2.8 (dd,2H), 1.6 (s,6H).

[0492] Example 129 & 130: ¹H NMR (400 MHz, d4-MeOH): d 8.76 (s,1H), 8.50(t,1H), 7.92 (dt,2H), 7.43 (q,1H), 6.90 (t,1H), 5.20 (m,1H), 4.90 (m),4.30 (m,1H), 4.20 (m,1H), 3.7-3.4 (m), 3.30 (s,2H), 3.20 (m,1H), 2.80(dd,2H), 1.60 (s,6H).

[0493] Example 137: ¹H NMR (300 MHz, d4-MeOH): d 4.7 (1,1H), 8.45(t,1H), 7.9 (t,2H), 7.25 (m,4H), 5.2 (m,1H), 4.95 (d,1H), 4.6 (s,2H),4.3 (m,1H), 3.8 (t,2H), 3.5 (dd,2H), 2.8 (m,1H), 2.8 (dd,2H), 1.6(s,6H).

[0494] Example 138: ¹H NMR (400 MHz, d4-MeOH): d 8.8 (dd,1H), 8.6(s,1H), 8.5 (t,1H), 7.95 (t,1H), 7.9 (s,1H), 7.3 (s,1H), 7.0 (s,1H), 5.2(s,1H), 4.85 (s,3H), 4.4 (m,1H), 4.18 (m,1H), 3.8 (m,2H), 3.5 (dd,2H),3.2 (d,2H), 2.8 (dd,2H), 1.6 (s,6H).

[0495] Example 141 & 142: ¹H NMR (300 MHz, d4-MeOH): d 8.75 (m,1H), 8.5(m,1H), 7.9 (m,2H), 7.3 (s,2H), 5.2 (m,1H), 4.65 (m,1H), 4.55 (s,2H),4.35 (m,1H), 4.20 (m,1H), 3.8 (t,1H), 3.5 (dd,2H), 3.15 (d,1H), 2.8(dd,2H), 1.6 (s,2H).

EXAMPLES 160-179

[0496] Examples 160 to 179 shown in the table below were preparedaccording to the scheme illustrated below by coupling the appropriatelysubstituted pyrazalone-piperidine I (in the scheme) with the (D)-Trpderivative (III) (see Example 2C) in an analogous manner to theprocedures described in Examples 3E and 3F.

R¹ = —CH₂—A¹ Ex. # Isomer R² A¹ MS MS Method 160 d1 Me 4-CF₃—Ph 584 APCI161 d1,2 Me 4-CF₃—Ph 584 APCI 162 d1 Me 4-F—Ph 533 PB 163 d2 Me 4-F—Ph533 PB 164 d1 Me 4-Ph—Ph 591 APCI 165 d1,2 Et 2,4-di-Cl—Ph 597 APCI 166d1,2 Et 2,4-F—Ph 566 APCI 167 d1 Et 4-CF₃—Ph 598 APCI 168 d1,2 Et4-CF₃—Ph 598 APCI 169 d1 Et 4-Cl—Ph 563 PB 170 d2 Et 4-Cl—Ph 563 PB 171d1,2 Et 4-F—Ph 547 APCI 172 d1,2 Et 4-Me—Ph 543 APOI 173 d1,2 CF₃CH₂2,4-di-Cl—Ph 651.5 APCI 174 d1,2 CF₃CH₂ 2,4-di-F—Ph 620 APCI 175 d1CF₃CH₂ 4-Cl—Ph 617 PB 176 d2 CF₃CH₂ 4-Cl—Ph 617 PB 177 d1 CF₃CH₂ 4-F—Ph601 APCI 178 d2 CF₃CH₂ 4-F—Ph 601 APCI 179 d1,2 CF₃CH₂ 4-Me—Ph 597 APCI

EXAMPLES 180-183

[0497] Examples 180 to 183 shown in the table below were preparedaccording to the scheme illustrated below by coupling the appropriatelysubstituted pyrazalone-piperidine I with the acid intermediate IV in ananalogous manner to the procedures described in Examples 3E and 3F.

[0498] The acid intermediate (IV) was prepared by treating an amino acidwith the product from Example 5D using the established proceduredescribed in Example 5F.

Iso- R² = —CH₂—A¹ Ex. # mer R² A¹ Ar MS Method 180 d1,2 Me Phenyl(CH₂)₂Ph 504 PB 181 d1,2 Me Phenyl SCH₂Ph 559 PB 182 d1 Me Phenyl2-Naphthalenyl 527 APCI 183 d1,2 Me Phenyl CH₂O-(4-F—Ph) 524 PB

EXAMPLE 184

[0499]2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,L-tartrate

[0500] A. 4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-ethyl ester

[0501] To a solution of 4-oxo-piperidine-3-carboxylic acid ethyl esterhydrochloride (100 g, 0.482 mol) in IPE (725 mL) and water (360 mL) wasslowly added TEA (63.5 g, 0.627 mol), followed by (Boc)₂O (115.7 g, 0.53mol). The mixture was stirred overnight under nitrogen. The organicphase was separated and washed with water and dried over Na₂SO₄, andconcentrated in vacuo to afford the desired product as crystals (142.9g, yield 109%, containing a small amount of IPE).

[0502] B. 3-Benzyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-ethyl ester

[0503] To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (73.36 g, 0.27 mol) in DMF (734 mL)lithium carbonate (50 g, 0.676 mol) was added, followed by benzylbromide (55.44 g, 0.324 mol). The mixture was heated to about 60° C. andstirred for about 20 hours. The reaction mixture was then cooled to roomtemperature and extracted with IPE, washed with water and dried overmagnesium sulfate. After filtration and concentration in vacuo a solidwas obtained. Recrystallization of the crude product in hexane affordeda white solid (33.6 g, yield 38.2%).

[0504] C.3a-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

[0505] To a solution of 3-benzyl-4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (1935.97 g, 5.36 mol) in toluene (9700mL) was added methylhydrazine (299.2 mL, 5.63 mol), followed by aceticacid (325 mL, 5.68 mol) slowly at about 8° C. The reaction mixture washeated slowly to about 65° C. and stirred for about 7.5 hours. Aftercooling to room temperature, the organic layer was washed with 10%sodium bicarbonate, water and saturated NaCl solution and concentratedin vacuo to a low volume. The reaction was repeated at same scale twice.The concentrated product solutions from the three reactions werecombined and mixed with IPE (50 L), cooled to about 0° C., HCl gas wasintroduced repeatedly and stirred at room temperature overnight untilthe deprotection was complete. The mixture was concentrated in vacuo toabout half of the original volume, methylene chloride (24 L) was added,followed by NH₄OH (22 L). The mixture was then extracted with methylenechloride and concentrated to a low volume (6 to 7 L). Hexane (20 L) wasadded and the mixture was cooled to about 15-20° C. The free baseproduct was collected as crystals and dried under vacuum (2985 g total,yield 84.8%.

[0506] D.3a-(R)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one,L-tartrate

[0507] To a solution of3a-(R)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(100 g, 0.41 mol) in a mixture of acetone/water (970 mL/120 mL) wasadded L-tartaric acid (67.55 g, 0.45 mol). The mixture was heated toabout 50° C. and stirred over night. The reaction mixture was cooled toabout 10-15° C. and precipitates were filtered, washed with coldacetone/water and dried under vacuum. The product was obtained as awhite solid (157.8 g, yield 97.83%, 99%ee).

[0508] E. 2-tert-Butoxycarbonaylamino-2-methyl-propionic acid

[0509] 2-Aminoisobutyric acid (140g, 1.36 mol), 1 N NaOH (1620 mL, 1.63mol, (Boc)₂O (375 mL, 1.63 mol) and THF 420 mL were mixed together andstirred at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate (700 mL) and adjusted to about pH 3.0 by adding 6 NHCl. The organic phase seperated was washed with saturated NaCl solutionand concentrated to approximately ¼ of the original volume. Aftertreatment with hexane a white solid product was isolated and collected(125.8 g, yield 45.44%). An additional 7.8 g of product was recoveredfrom the mother liquor.

[0510] F. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid2,5-dioxo-pyrrolidin-1-yl ester

[0511] To a solution of 2-tert-Butoxycarbonylamino-2-methyl-propionicacid (100 g, 0.492 mol) and succinic anhydride (60.02 g, 0.522 mol) inmethylene chloride (1000 mL) was added EDC (100.09 g, 0.522 mol) whilestirring under nitrogen. The mixture was stirred under nitrogenovernight. The reaction mixture was then diluted with ethyl acetate (1L), washed with saturated sodium bicarbonate solution and water, thenconcentrated in vacuo to a low volume. White crystals precipitated outof solution and were collected by filtration and dried under vacuum toafford the product (104.9 g+27.3 g, yield 89.5%).

[0512] G.3-(R)-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid

[0513] To a solution of 2-amino-3-benxyloxy-propionic acid (26.2 g,0.113 mol) in water (101.8 mL) and TEA (28.53 g. 0.282 mol) was added2-tert-butoxycarbonylamino2-methyl-propionic acid2,5-dioxo-pyrrolidin-1-yl ester (33.94 g, 0.113 mol) in THF (407 mL).The mixture was stirred overnight at room temperature under nitrogen. A10% citric acid solution (500 mL) was added to the mixture. The mixturewas stirred for another 10 min., then diluted with ethyl acetate (500mL). The organic phase was seperated from the mixture and washed withwater and saturated NaCl solution and then concentrated in vacuo to athick oil. The crude oil was treated with IPE/hexane (50/50) and cooledato about 10° C. to afford a white solid product (42.3 g, yield 98.4%).

[0514] H.{1-[2-(3a-(R)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbomoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0515] To a solution of3a-(R)-Benzyl-2-methyl-2,3,3a,4,6,7-hexahydro-pyrazolo]4,3-c]pyridin-3-one,L-tartate (10.81 g, 0.0275 mol) in ethylo acetate (216.2 mL) at about−66° C. was added TEA (8.43 mL, 0.0605 mol). The mixture was stirred forabout 1.5 hours. After removal of the precipitated salt by filtration,3-benzyloxy-2-(2-tert-butozycarbonylamino-2-methyl-propionylamino)-propionicacid (8.7 g. 0.0229 mol) and TEA (19.15 mL, 0.1374 mol) were added atabout −35° C., followed by the dropwise addition of 50% PPAA in ethylacetate (27.5 mL, 0.0458 mol). The mixture was stirred for about 2 hoursat about −20° C. to about −27° C., then 1.5 hours while the temperaturewas slowly raised to about 0° C. The reaction mixture was poured intowater and extracted with IPE, washed with 7% NaCl solution andconcentrated in vacuo. The crude oil that was obtained was treated withIPE/hexane (50/50)to allow crystillization. The product was obtained asa white solid (10.3 g, yield 74.3%).

[0516] I.2-Amino-N-[2-(3a-(R)-benxyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide

[0517] To a solution of{1-[2-(3a-(R)-benxyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert butyl ester (10.3 g, 0.017 mol) in methylene chloride (68.6mL) at about 0-5° C. was added TFA 35 mL) to maintain the temperaturebelow about 5° C. THe terperature was then raised to room tempertature.The mixing was stirred for about 3 hours. Methylene chloride wasreplaced with ethyl acetate as a solvent. The mixture was then adjustedto about pH 8 with a saturated sodium bicarbonate solution, then washedwith saturated NaCl and concentrated in vacuo to a low volume. A whitesolid product was obtained after treating the mixture with IPA and thenhexan (7.4g, yield 86.1%). HPLC showed product containing 0.2%diastereomer.

[0518] J.2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,L-tartrate

[0519] To a solution of2-amino-N-[-2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamidefrom step I (385 g, 0.761 mol) in methanol (4000 mL) was addedL-(+)-tartaric acid (114.5 g, 0.761 mol) and the mixture was stirredovernight. The resulting hazy solution was filtered yielding a clearsolution which was concentrated to remover most of the solvent. Ethylacetate (total 12 L) was added and the remaining methanol was removedazeotropically between about 63 and 72° C. The solid that was isolatedwas dissolved in ethyl acetate and the solution was refluxed for about16 hours, then allowed to cool to room temperature overnight. Theproduct was collected as a white solid (482.3 g, yield 96.8%), M.P.174-176° C.

EXAMPLE 185

[0520]2-Amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide L-(+)tartrate

[0521] A. 4-Oxo-3-pyridin-2-ylmethyl-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester

[0522] To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (10.34 g, 38.2 mmol) in DMF (40 mL) atabout 0° C. was added picolyl chloride hydrochloride (5.7 g, 34.7 mmol),potassium carbonate (14.4 g, 104.1 mmol) and potassium iodide (5.76 g,34.7 mmol). After stirring at about 0° C. for about 2 hours, the icebath was removed and DABCO (973 mg, 8.68 mmol) was added. The reactionmixture was stirred for about 30 min. and poured into a mixture of waterand IPE. The organic layer was separated and washed with saturatedaqueous NaHCO₃ and saturated aqueous NaCl, dried over Na₂SO₄ andconcentrated in vacuo. The crude residue was crystallized from hexanesto give a white solid (8.19 g, yield 65%). ¹H-NMR (CDCl₃) δ1.17 (t,3H),1.48 (s,9H), 1.55 s, 2H), 2.61 (m, 1H), 2.71 (m, 1H), 3.31-3.50 (m,3H),4.11 (d, 1H), 7.06 (br s, 1H), 7.17(d, 1H), 7.54 (m, 1H), 8.40 (s,1H).

[0523] B.3-Oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxyylicacid tert-butyl ester

[0524] A 70% aqueous solution of CF₃CH₂NNNH₂ (325 mL, 1.986 mol)(obtained from Aldrich) was extracted with toluene (3×1200 mL). To asolution of the product from step A (600 g, 1.655 mol) in toluene (900mL) was first added the combined toluene extracts containing theanhydrous 2,2,2-triflouroethyl hydrazine, followed by acetic acid (121.4g, 1.986 mol). The reaction mixture was heated at about 70% aqueous2,2,2-triflouroethyl hydrazine (50 g) was added. The reaction mixturewas heated at about 80° C. for about 3.5 hours, cooled to roomtemperature and diluted with saturated aqueous NAHCO₃(2 L). The toluenelayer was separated and washed with saturated aqueous NaCl, dried overNa₂SO₄ and concentrated in vacuo to give an oil (754.8 g).Crystallization from methanol/water afforded the desired product as awhite solid (609.5 g). ¹H-NMR (CDCl₃) δ 150 (s, 9H), 2.53 (d, 1H), 2.70(br s, 2H), 2.88 (br s, 1H), 3.31 (m, 2H), 3.97 (m, 1H),4.19 (m, 1H),2.88 (br s, 1H),3.31 (m, 2H), 3.97 (m, 1H), 4.19 (m,1H), 4.63 (br s, 1H,7.06 (m,2H), 7.51(m, 1H), 8.34(m, 1H).

[0525] C.3a-Pyridin-2-ylmethyl-2,2,2-trifluoroethyl)-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

[0526] Methanesulfonic acid (11.6 g, 121 mmol) was added dropwise to asolution of the product from set B (10 g, 24.2 mmol) in CH₂Cl₂ (100 mL)over about 30 minutes. The reaction mixture was stirred for about 1 hourthen cooled to about 0° C., and then triethylamine (18.6 mL, 133.1 mmol)was added through an addition funnel. The mixture was allowed to warm toroom temperature over about 1 hour, diluted with additional CH₂Cl₂ andwashed with saturated aqueous NaCl, dried over Na₂SO₄, filtered andconcentrated in vacuo to affor the product as a white solid (7.2 g).¹H-NMR (CDCl₃)δ:2.51-2.72 (m, 4H), 3.35 (m, 2H), 4.03 (m, 1H), 4.25 (m,1H), 4.25 (m, 1H), 7.08 (d, 2H), 7.51 (t, 1H), 8.37 (d, 1H).

[0527] D.3a-Pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-2,3-a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(D)-tartrate

[0528] In a dry and nitrogen purged 5 L round bottom flask equipped witha mechanical stirrer, D-(−) tartaric acid 129 g, 0.86 mol) was added tothe product from step C (243 g, 0.78 mol) in acetone/water (9:1, 2430mL) at about 17° C. The mixture was stirred at room temperatureovernight, filtered, the solid was collected and washed with coldacetone and dried under vacuum. The product was obtained as a yellowsolid (284 g, yield 78.8%).

[0529] E.2-tert-Butoxycarbonylamino-3-(2,4-difluoro-benzyloxy)-propionic acid

[0530] To a solution of N-Boc-(D)-serine (452 g, 2.2026 mol) in amixture of THF (7L) and DMF (3L) at about 0° C. was added potassiumtert-butoxide solution (515.8 g, 4.5963 mol). The reaction mixture wasstirred at about 0° C. for about 30 min., then 2,4-difluorobenzylbromide (456.5 g, 2.2051 mol) was added. After warming to roomtemperature, the reaction mixture was concentrated in vacuo to removethe THF. The reaction mixture was partitioned between 4.5 L H₂O and 4.5L IPE. The layers were saparated and the pH of the aqueous layer wasadjusted with 1 N HCl to about 3. The aqueous layer was extracted twicewith 4 L each of IPE. The organic solution was dried over Na₂SO₄, andconcentrated in vacuo to yield a yellow waxy solid (518.0 g, yield:70.9%). ¹H-NMR (CDCl₃) δ 1.44 (s, 9H), 3.73 (m, 1H), 3.94 (d, 1H), 4.44(br s, 1H), 4.54 (s, 2H), 5.34 (m, 1H), 6.78 (m, 1H), 6.84 (m, 1H), 7.30(m, 1H).

[0531] F. 2-Amino-3-(2,4-difluoro-benzyloxy)-propionic acid,methanesulfonic acid salt

[0532] To a solution of the product from step E (1.19 g, 3.59 mmol) inCH₂Cl₂/IPE (1:1, 12 mL) was added methanesulfonic acid (1.72 g, 17,95mmol) through a syringe over about 10 minutes. A solid immediatelyprecipitated out of solution. After about 1 hour, the solid was filteredand washed with a CH₂Cl₂/IPE mixture (1:1) to afford 939 mg of product(yield 80%).

[0533] G.2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(2,4-difluoro-benzyloxy)-propionicacid

[0534] To a solution of the product from step F (520 mg, 1.46 mmol) inTHF/water (4:1, 10 mL) was added2-tert-butoxycarbonylamino-2-methyl-propionicacid-2,5-dioxo-pyrrolidin-1-yl ester (438 mg, 1.46 mmol) andtriethylamine (369 mg, 3.65 mmol). The reaction mixture was stirred atroom temperature for about 1 hour and quenched with a 10% aqueous citricacid solution (10 mL). After about 15 min., ethyl acetate (50 mL) wasadded and the organic layer was separated and washed with saturatedaqueous NaCl, dried over Na₂SO₄ and concentrated in vacuo to give a foam(534.1 mg, yield 88%). ¹H-NMR (CD₃OD): δ1.38 (br s, 15H), 3.77 (d, 1H),3.92(d, 1H), 4.52(m, 3H), 6.92 (m, 1H), 7.41 (m, 1H), 7.58 (d, 1H).

[0535] H.(1-{-(2,4-Difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

[0536] (a) The product from step D (517 g, 1.12 mol) was added at about−30° C. to ethyl acetate (5170 mL) in a dry and nitrogen purged 12 Lround bottom flask equipped with a mechanical stirrer. The solution wascooled to about −40° C., then triethylamine (398 mL, 2.86 mol) was addedover about 45 minutes. The reaction mixture was stirred for about 90min. at a temperature between about −50° C. and about −40° C., filteredinto a 22 L round bottom flask purged with nitrogen and washed withethyl acetate (2068 mL, pre-cooled to about −50° C. ) to give the freebase as a white solid.

[0537] (b) The product from G (425 g, 1.02 mol) was added at about −30°C. to an ethyl acetate solution containing the product from step H(a),triethylamine (654 mL, 4.69 mol) and PPAA (50% in ethyl acetate, 916 mL,1.53 mol). The reaction mixture was stirred for about 1 hour, washedwith water and saturated aqueous NaCl, dried over Na₂SO₄ andconcentrated in vacuo to give the product as an oil (636 g, yield:87.8%).

[0538] I.2-Amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide

[0539] Methanesulfonic acid (258.3 mL, 3.98 mol) was added dropwise atabout 15° C. over about 55 minutes to the product from step H (566 g,0.796 mol) in CH₂Cl₂ (11,320 mL) in a dry and nitrogen purged 22 L roundbottom flask equipped with a mechanical stirrer. The mixture was stirredfor about 40 minutes at about 20° C., then saturated aqueous NaHCO₃(8,490 mL) was added until the pH was about 7.8. The organic layer wasseparated, washed with water and saturated aqueous NaCl, dried overNa₂SO₄, and concentrated in vacuo to afford an oily product (388.8 g,yield 80%).

[0540] J.2-Amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamideL-(+) tartrate

[0541] To a solution of product from step I (370 g, 0.6 mol) in methanol(4,070 mL) in a 12 L round bottom flask equipped with a mechanicalstirrer was added L-(+) tartaric acid (90 g, 0.6 mol). The reactionmixture was stirred for about 90 min. at about 22° C., filtered andconcentrated. The crude residue was diluted with ethyl acetate (4,560mL), heated at about 70° C. and slowly allowed to cool to roomtemperature over about 17 hours. The solid was filtered and dried togive white crystals, mp 188-189° C. (348.46 g, yield 76%). ¹NMR (MeOH,d4) δ:8.28 (d, 1H), 7.59 (t, 1H), 7.41-7.39 (m, 1H), 7.18-7.13 (m, 1H),6.92 (t, 1H), 5.2 (t, 1H), 4.56 (bs, 3H), 4.36 (s, 2H), 4.31-4.25 (m,1H), 4.13-4.06 (m, 1H), 3.78 (d, 2H), 3.21 (t, 1H), 3.18-2.96 (m, 2H),2.65-2.55 (m, 2H), 1.57 (d, 6H). MS: MH+611. [a]⁵⁸⁹+22.03 (c=11.9,MeOH).

EXAMPLE A

[0542] The following are the result of the “Female Rat Study” describedhereinabove wherein the rats were administered the GH secretagoguecompound2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(benzyloxymethyl)-2-oxo-ethyl]-isobutyramideL-tartaric acid salt. TABLE 1 Mean Plasma Insulin and Metabolite LevelsAfter Daily Dosing of a GHRP Mimetic for Three Months Choles- DoseInsulin Glucose Lactate terol Triglyceride Surgery (mg/kg) (uU/mL)(mg/dl) (mg/dl) (mg/dl) (mg/dl) Sham Vehicle 118.8 181.7 4.6 97.9 254.8Sham 0.5 94.9 *142.7 3.7 95.4 219.6 Sham 5.0 95.7 *139.9 *3.2 *80.6227.2 Ovx Vehicle 112.8 194.0 3.9 106.8 182.7 Ovx 0.5 *78.7 179.7 3.692.5 181.9 Ovx 5.0 *84.1 177.2 3.1 102.2 158.4

[0543] Data in Table 1 show that this treatment is associated withdose-related lowering of plasma glucose and/or insulin levels, which isconsistent with an improvement in glycemic control and insulinsensitivity by this treatment. The treatment was also associated withtrends for decreased plasma lactate, cholesterol and triglyceridelevels, which is also consistent with an improvement in lipid profileand metabolic control as a result of improved insulin sensitivityincurred by this treatment.

What is claimed is:
 1. A method for treating insulin resistance in amammal, which comprises administering to said mammal an effective amountof a compound of formula I

or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers, or the pharmaceutically acceptable salts and prodrugsthereof, wherein e is 0 or 1 ; n and w are each independently 0, 1 or 2;provided that w and n cannot both be 0 at the same time; Y is oxygen orsulfur; p1 R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or—OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) groupand (CH₂)_(t) group may each be optionally substituted with hydroxyl,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyleater, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C₁-C₄)alkyl; R² ishydrogen, (C₁-C₈)alkyl, -(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen; R³ is A¹, (C₁-C₁₀)alkyl,-(C₁-C₆)alkyl-A¹, -(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl, -(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen,(C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ andthe carbon atom to which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a)is optionally substituted with a substituent selected from the groupconsisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); or the carbon bearingX⁵ or X^(5a) forms one or two alkylene bridges with the nitrogen atombearing R⁷ and R⁸ wherein each alkylene bridge contains 1 to 5 carbonatoms, provided that when one alkylene bridge is formed then X⁵ orX^(5a) but not both may be on the carbon atom and R⁷ or R⁸ but not bothmay on the nitrogen atom and further provided that when two alkylenebridges are formed the X⁵ and X^(5a) cannot be on the carbon atom and R⁷and R⁸ cannot be on the nitrogen atom; or X⁵ is taken together withX^(5a) and the carbon atom to which they are attached and form apartially saturated or fully saturated 3- to 7-membered ring, or apartially saturated or fully saturated 4- to 8-membered ring having 1 to4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen; or X⁵ is taken together with X^(5a) and thecarbon atom to which they are attached and form a bicyclic ring systemconsisting of a partially saturated or fully saturated 5- or 6-memberedring, optionally having 1 or 2 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; Z¹ isa bond, O or N—X², provided that when a and b are both 0 then Z¹ is notN—X² or O; R⁷ and R⁸ are independently hydrogen or optionallysubstituted (C₁-C₆)alkyl; where the optionally substituted (C₁-C₆)alkylin the definition of R⁷ and R⁸ is optionally independently substitutedwith A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1to 3 hydroxy, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or R⁷and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—; where L isC(X²)(X²), S(O)_(m) or N(X²); A¹ for each occurrence is independently(C₅-C₇)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen; A¹ for each occurrenceis independently optionally substituted, in one or optionally both ringsif A¹ is a bicyclic ring system, with up to three substituents, eachsubstituent independently selected from the group consisting of F, Cl,Br, l, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶, —C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶), —SO₂N(X⁶)(X⁶), —N(X⁶) SO₂-phenyl,—N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², —NX⁶SO₂X¹², —NX⁶CONX¹¹X¹²,—NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl,provided that if A¹ is optionally substituted with methylenedioxy thenit can only be substituted with one methylenedioxy; where X¹¹ ishydrogen or optionally substituted (C₁-C₆)alkyl; the optionallysubstituted (C₁-C₆)alkyl defined for X¹¹ is optionally independentlysubstituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² is hydrogen,(C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, X¹² is optionally substituted with one tothree substituents independently selected from the group consisting ofCl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together toform —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²), O, S(O)_(m) orN(X²); r for each occurrence is independently 1, 2 or 3; X² for eachoccurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³; X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;X⁶ is independently hydrogen, optionally substituted (C₁-C₆)alkyl,(C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl in the definition of X⁶ is optionally independentlysubstituted by 1 or 2 (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy, carboxyl,CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester, or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C_(a)-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9- membered ring optionally having oxygen,sulfur or NX⁷; X⁷ is hydrogen or (C₁-C₆)alkyl optionally substitutedwith hydroxyl; and m for each occurrence is independently 0, 1 or 2;with the proviso that: X⁶ and X¹² cannot be hydrogen when it is attachedto C(O) or SO₂ in the form C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²; and when R⁶is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 2. A method accordingto claim 1 wherein said compound of formula I is of the followingformula

or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers, or the pharmaceutically acceptable salts and prodrugsthereof where R¹ is —CH₂-phenyl, R² is methyl and R³ is —(CH₂)₃-phenyl;R¹ is —CH₂-phenyl, R² is methyl and R³ is 3-indolyl-CH₂—; R¹ is—CH₂-phenyl, R² is ethyl and R³ is 3-indolyl-CH₂—; R¹ is—CH₂-4-fluoro-phenyl, R² is methyl and R³ is 3-indolyl-CH₂—; R¹ is—CH₂-phenyl, R² is methyl and R³ is —CH₂—O—CH₂-phenyl; R¹ is—CH₂-phenyl, R² is ethyl and R³ is —CH₂—O—CH₂-phenyl; R¹ is —CH₂-phenly,R² is —CH₂CF₃ and R³ is —CH₂—O—CH₂-phenyl; R¹ is —CH₂-4-fluoro-phenyl,R² is methyl and R³ is —CH₃—O—CH₂-phenyl; R¹ is —CH₂-phenyl, R² ist-butyl and R³ is —CH₂—O—CH₂-phenyl; or R¹ is —CH₂-phenyl, R² is methyland R³ is —CH₂—O—CH₂-3,4-di-fluoro-phenyl.
 3. A method according toclaim 1 wherein said compound of formula I is of the formula

or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers or the pharmaceutically acceptable salts and prodrugsthereof where R² is methyl; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-phenyl; R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-3-chloro-phenyl; R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-4-chloro-phenyl; R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-2,4-di-chloro-phenyl; R² is CH₂CF₃; A¹ is 2-pyridyl; and R³is —CH₂—O—CH₂-3-chloro-thiophene or R² is CH₂CF₃; A¹ is 2-pyridyl; andR³ is —CH₂—O—CH₂-2,4-di-fluoro-phenyl.
 4. A method according to claim 1wherein said compound of formula I or the stereoisomeric mixtures,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomers or the pharmaceuticallyacceptable salts and prodrugs thereof is the 3a(R,S),1(R) diastereomericmixture, the 3a(R),1(R) diastereomer or the 3a(S),1(R) diastereomer of acompound selected from the group consisting of2-amino-N-[1-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-bytyl]-isobutyramide,2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide,2-amino-N-[1-(3a-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide,2-amino-N-[2-(3a-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide,2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,2-amino-N-[1-(3a-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,2-amino-N-{2-[3a-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-benzyloxymethyl-2-oxo-ethyl}-isobutyramide,2-amino-N-{1-benzyloxymethyl-2-[3a-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramide,2-amino-N-[2-(3a-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-[2-(3a-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-isobutyramide.5. A method according to claim 4 wherein said compound is2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideL-tartaric acid salt.
 6. A method according to claim 1 wherein saidcompound of formula I or the stereoisomeric mixtures, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomers or the pharmaceutically acceptable saltsand prodrugs thereof is the 3a-(R,S),1-(R) diastereomeric mixture, the3a-(R),1-(R) enantiomer or 3a-(S),1-(R) enantiomer of a compoundselected from the group onsisting of2-amino-N-[1-benzyloxymethyl-2-(2-methyl-3-oxo-3a-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide;2-amino-N-{1(3-chloro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide;2-amino-N-{1(4-chloro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide;2-amino-N-{1(2,4-dichloro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide;2-amino-N-{1(4-chloro-thiophen-2-ylmethoxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,5,7-hexahydro-pyrazolo[3,4-c]pyridin-6-yl]-ethyl}-2-methyl-propionamide;and2-amino-N-{1(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide.7. A method for treating insulin resistance in a mammal according toclaim 1 which additionally comprises administering to a mammal in needthereof a growth hormone releasing hormone or a functional analogthereof.
 8. A pharmaceutical composition useful for treating insulinresistance in a mammal which comprises a pharmaceutically acceptablecarrier and an effective amount of a compound of formula I

or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers or the pharmaceutically acceptable salts and prodrugsthereof, wherein e is 0 or 1; n and w are each independently 0, 1 or 2;provided that w and n cannot both be 0 at the same time; Y is oxygen orsulfur; R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C⁶)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)-Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or—OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) groupand (CH₂)_(t) group may each be optionally substituted with hydroxyl,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C₁-C₄)alkyl; R² ishydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen; R³ is A¹, (C₁-C₁₀)alkyl,—(C₁-C₆)alkyl-A¹, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl, —(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or—(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen,(C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ andthe carbon atom to which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a)is optionally substituted with a substituent selected from the groupconsisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); or the carbon bearingX⁵ or X^(5a) forms one or two alkylene bridges with the nitrogen atombearing R⁷ and R⁸ wherein each alkylene bridge contains 1 to 5 carbonatoms, provided that when one alkylene bridge is formed than X⁵ orX^(5a) but not both may be on the carbon atom and R⁷ or R⁸ but not bothmay be on the nitrogen atom and further provided that when two alkylenebridges are formed then X⁵ and X^(5a) cannot be on the carbon atom andR⁷ and R⁸ cannot be on the nitrogen atom; or X⁵ is taken together withX^(5a) and the carbon atom to which they are attached and form apartially saturated or fully saturated 3- to 7-membered ring, or apartially saturated or fully saturated 4- to 8-membered ring having 1 to4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen; or X⁵ is taken together with X^(5a) and thecarbon atom to which they are attached and form a bicyclic ring systemconsisting of a partially saturated or fully saturated 5- or 6-memberedring, optionally having 1 or 2 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; Z¹ isa bond, O or N—X², provided that when a and b are both 0 then Z¹ is notN—X² or O; R⁷ and R⁸ are independently hydrogen or optionallysubstituted (C₁-C₆)alkyl; where the optionally substituted (C₁-C₆)alkylin the definition of R⁷ and R⁸ is optionally independently substitutedwith A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1to 3 hydroxy, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or R⁷and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—; where L isC(X²)(X²), S(O)_(m) or N(X²); A¹ for each occurrence is independently(C₅-C₇)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen; A¹ for each occurrenceis independently optionally substituted, in one or optionally both ringsif A¹ is a bicyclic ring system, with up to three substituents, eachsubstituent independently selected from the group consisting of C, Cl,Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶, —C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², —NX⁶SO₂X¹²,—NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl, thiazolyl andtetrazolyl, provided that if A¹ is optionally substituted withmethylenedioxy then it can only be substituted with one methylenedioxy;where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² is hydrogen,(C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, X¹² is optionally substituted with one tothree substituents independently selected from the group consisting ofCl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together toform —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²), O, S(O)_(m) orN(X²); r for each occurrence is independently 1, 2 or 3; X² for eachoccurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³; X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;X⁶ is independently hydrogen, optionally substituted (C₁-C₆)alkyl,(C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl,(C₃-C₇)-halogenatedcycloalkyl, where optionally substituted (C₁-C₆)alkyland optionally substituted (C₃-C₇₆)cycloalkyl in the definition of X⁶ isoptionally independently substituted by 1 or 2 (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate(C₁-C₄)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X⁶ groupson one atom and both X⁶ are independently (C₁-C₆)alkyl, the two(C₁-C₆)alkyl groups may be optionally joined and, together with the atomto which the two X⁶ groups are attached, form a 4- to 9-membered ringoptionally having oxygen, sulfur or NX⁷; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxyl; and m for each occurrence isindependently 0, 1 or 2; with the proviso that: X⁶ and X¹² cannot behydrogen when it is attached to C(O) or SO₂ in the form C(O)X⁶, C(O)X¹²,SO₂X⁶ or SO₂X¹²; and when R⁶ is a bond then L is N(X²) and each r in thedefinition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 9. A methodfor increasing levels of endogenous growth hormone, which comprisesadministering to a human or other animal in need thereof effectiveamounts of a functional somatostatin antagonist and a compound offormula I

or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers or the pharmaceutically acceptable salts and prodrugsthereof, wherein e is 0 or 1; n and w are each independently 0, 1 or 2;provided that w and n cannot both be 0 at the same time; Y is oxygen orsulfur; R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)₁C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or—OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) groupand (CH₂)_(t) group may each be optionally substituted with hydroxyl,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C₁-C₄)alkyl; R² ishydrogen, (C₁-C₈)alkyl-(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, -(C₁-C₄)alkyl-A¹or A¹; where the alkyl groups and cycloalkyl groups in the definition ofR² are optionally substituted with hydroxyl, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2, or 3halogen; R³ is A¹, (C₁-C₁₀)alkyl, -(C₁-C₆)alkyl,-(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, -(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,-(C₁-C₅)alkyl-X¹-C₀-C₅)alkyl-A¹ or-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4, or 5 halogens, or 1, 2 or 3OX³; X¹ is O, S(O)_(m), —N(X²)C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen, (C₁C₆)alkyl or(C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ and the carbon atomto which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; X⁴ishydrogen or C₁-C₆)alkyl or X⁴ is taken together with R⁴ and the nitrogenatom to which X⁴ is attached and the carbon atom to which R⁴ is attachedand form a five to seven membered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a)is optionally substituted with a substituent selected from the groupconsisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); or the carbon bearingX⁵ or X^(5a) forms one or two alkylene bridges with the nitrogen atombearing R⁷ and R⁸ wherein each alkylene bridge contains 1 to 5 carbonatoms, provided that when one alkylene bridge is formed then X⁵ orX^(5a) but not both may be on the carbon atom and R⁷ or R⁸ but not bothmay be on the nitrogen atom and further provided that when two alkylenebridges are formed the X⁵ and X^(5a) cannot be on the carbon atom and R⁷and R⁸ cannot be on the nitrogen atom; or X⁵ is taken together withX^(5a) and the carbon atom to which they are attached and form apartially saturated or fully saturated 3- to 7-membered ring, or apartially saturated or fully saturated 4- to 8-membered ring having 1 to4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen; or X⁵ is taken together with X^(5a) and thecarbon atom which they are attached and form a bicyclic ring systemconsisting of a partially saturated or fully saturated 5- or 6-memberedring, optionally having 1 or 2 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; Z¹ isa bond, O or N-X², provided that when a and b are both 0 then Z¹ is notN—X² or O; R⁷ and R⁸ are independently hydrogen or optionallysubstituted (C₁-C₆)alkyl; where the optionally substituted (C₁-C₆)alkylin the definition of R⁷ and R⁸ is optionally independently substitutedwith A¹, —C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1to 3 hydroxyl, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; orR⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r); where Lis C(X²)(X²), S(O)_(m) or N(X²); A¹ for each occurrence is independently(C⁵-C⁷)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen; A¹ for each occurenceis independently optionally substituted, in one or optionally both ringsif A¹ is a bicyclic ring system, with up to three substituents, eachsubstituent independently selected from the group consisting of F, Cl,Br, I, OCF₃, OCF₂H, CF₃, OCH₃, —X₃, —C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylaklyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—NX⁶CONX¹¹X¹², —NX⁶SO₆SO₂NX¹¹X¹², imidazolyl, thiazolyl and tetrazolyl,provided that is A¹ is optionally substituted with methylenedioxy thenit can only be substituted with one methylenedioxy; where X¹¹ ishydrogen or optionally substituted (C₁-C₆)alkyl; the optionallysubstituted (C₁-C₆)alkyl defined for X¹¹ is optionally independentlysubstituted with phenyl, phenoxy, (C₁-C₆) alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 and 5 halogens, 1 to 3 hydrody, 1 or 3(C₁-C₁₀)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, X¹² is optionally substituted with one tothree substituted independently selected from the group consisting ofCl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together toform —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²), O, S(O)_(m) orN(X²); r for each occurence is independently 1, 2, or 3; X² for eachoccurence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇) cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³; X³ for each occurence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl; X⁶ is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionallysubstituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenatedcycloalkyl, whereoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X⁶ is optionally independentlysubstituted by 1 or 2 (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy, carboxyl,CONH₂,—S(O)_(m)(C₁-C₄)alkyl ester, or 1H-tetrazol-5yl; or when there aretwo X⁶ groups on one atom and both X⁶ are independently (C₁-C₆)alkyl,the two (C₁-C₆)alkyl groups may be optionally joined and, together withthe atom to which the two X⁶groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX⁷; X⁷ is hydrogen or(C₁-C₆)alkyl optionally substituted with hydroxyl; and m for eachoccurrence is independently 0, 1, or 2; with the proviso that: X⁶ andX¹² cannot be hydrogen when it is attached to C(O) or SO₂ in the formC(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²; and when R⁶ is a bond then L is N(X²)and each r in the definition —(CH₂—L—(CH₂)_(r)— is independently 2 or 3.10. A method of treating or preventing congestive heart failure, obesityor frailty associated with aging, which comprises administering to amammal in need thereof effective amounts of a functional somatostatinantagonist and a compound of formula I

or the stereoisomeric mixtures, diasteromerically enriched,diasteromerically pure, enantiomerically enriched or enantiomericallypure isomers or the pharmaceutically acceptable salts and prodrugsthereof, wherein e is 0 or 1, n and w are each independently 0, 1 or 2;provided that w and n cannot both be 0 at the same time; Y is oxygen orsulfur; R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X₆,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(r)—A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(r)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X₆), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or—OC(O)—; q is 0, 1, 2, 3, or 3; t is 0, 1, 2 or 3; said (CH₂)_(q) groupand (CH₂)_(t) group may each be optionally substituted with hydroxyl,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C₁-C₄)alkyl; R² ishydrogen, (C₁-C₈)alkyl, -(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen; R³ is A¹, (C₁-C₁₀)alkyl,-(C₁-C₆)alkyl-A¹, -(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl, -(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)—or —C≡C—; R⁴ is hydrogen,(C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ andthe carbon atom to which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partiallly saturated or fully saturated 5-or 6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethly, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally subsituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a) isoptionally substituted with a substituent selected from the groupconsisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); or the carbon bearingX⁵ or X^(5a) forms one or two alkylene bridges with the nitrogen atombearing R⁷ and R⁸ wherein each alkylene bridge contains 1 to 5 carbonatoms, provided that when one alkylene bridge is formed then X⁵ orX^(5a) but not both may be on the carbon atom and R⁷ or R⁸ but not bothmay be on the nitrogen atom and further provided that when two alkylenebridges are formed then X⁵ and X^(5a) cannot be on the carbon atom andR⁷ and R⁸ cannot be on the nitrogen atom; or X⁵ is taken together withX^(5a) and the carbon atom to which they are attached and form apartially saturated or fully saturated 3- to 7-membered ring, or apartially saturated or fully saturated 4- to 8-membered ring having 1 to4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen; or X⁵ is taken together with X^(5a) and thecarbon atom to which they are attached and form a bicyclic ring systemconsisting of a partially saturated or fully saturated 5- or 6-memberedring, optionally having 1 or 2 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; Z¹ isa bond, O or N—X², provided that when a and b are both 0 the Z¹ is notN—X^(2 or O;) R⁷ and R⁸ are independently hydrogen or optionallysubstituted (C₁-C₆)alkyl; where the optionally substituted (C₁-C₆)alkylin the definition of R⁷ and R⁸ is optionally independently substitutedwith A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1to 3 hydroxy, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or R⁷and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—; where L isC(X²)(X²), S(O)_(m) or N(X²); A¹ for each occurrence is independently(C₅-C₇)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen; A¹ for each occurrenceis independently optionally substituted, in one or optionaly both ringsif A¹ is a bicyclic ring system, with up to three substituents, eachsubstituent independently selected from the group consisting of F, Cl,Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶, —C(O)N(X⁶)(X⁶), —C(O)OX⁶,oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², —NX⁶SO₂X¹²,—NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl, thiazolyl andtetrazolyl, provided that if A¹ is optionally substituted withmethylenedioxy then it can only be substituted with one methylenedioxy;where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² is hydrogen,(C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, X¹² is optionally substituted with one tothree substituents independently selected from the group consisting ofCl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together toform —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²), O, S(O)_(m) orN(X²); r for each occurrence is independently 1, 2 or 3; X² for eachoccurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³; X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;X⁶ is independently hydrogen, optionally substituted (C₁-C₆)alkyl,(C₂-C₆)-halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl,(C₃-C₇)-halogenatedcycloalkyl, where optionally substituted (C₁-C₆)alkyland optionally substituted (C₃-C₇)cycloalkyl in the defintion of X⁶ isoptionally independently substituted by 1 or 2 (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate(C₁-C₄)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X⁶ groupson one atom and both X⁶ are independently (C₁-C₆)alkyl, the two(C₁-C₆)alkyl groups may be optionally joined and, together with the atomto which the two X⁶ groups are attached, form a 4- to 9- membered ringoptionally having oxygen, sulfur or NX⁷; X⁷ hydrogen or (C₁-C₆)alkyloptionally subtituted with hydroxyl; and m for each occurrence isindependently 0, 1 or 2; with the proviso that: X⁶ and X¹² cannot behydrogen when it is attached to C(O) or SO₂ in the form C(O)X⁶, C(O)X¹²,SO₂X⁶ or SO₂X¹²; and when R⁶ is a bond then L is N(X²) and each r in thedefinition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 to
 3. 11. A methodaccording to claim 10 wherein said functional somatostatin antagonist isan alpha-2 adrenergic-agonist.
 12. A method according to claim 11wherein said alpha-2 adrenergic agonist is selected from the groupconsisting of clonidine, xylazine and medetomidine.
 13. A methodaccording to claim 12 wherein said compound of formula I is2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideL-tartaric acid salt.
 14. A pharmaceutical composition which comprises apharmaceutically acceptable carrier, an amount of an alpha-2 adrenergicagonist and an amount of a compound of formula I

or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers or the pharmaceutically acceptable salts and prodrugsthereof, wherein e is 0 or 1; n and w are each independently 0, 1 or 2;provided that w and n cannot both be 0 at the same time; Y is oxygen orsulfur; R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C⁶)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or—OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) groupand (CH₂)_(t) group may each be optionally substituted with hydroxyl,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C₁-C₄)alkyl; R² ishydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen; R³ is A¹, (C₁-C₁₀)alkyl,—(C₁-C₆)alkyl-A¹, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl, —(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or—(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen,(C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ andthe carbon atom to which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a)is optionally substituted with a substituent selected from the groupconsisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); or the carbon bearingX⁵ or X^(5a) forms one or two alkylene bridges with the nitrogen atombearing R⁷ and R⁸ wherein each alkylene bridge contains 1 to 5 carbonatoms, provided that when one alkylene bridge is formed than X⁵ orX^(5a) but not both may be on the carbon atom and R⁷ or R⁸ but not bothmay be on the nitrogen atom and further provided that when two alkylenebridges are formed then X⁵ and X^(5a) cannot be on the carbon atom andR⁷ and R⁸ cannot be on the nitrogen atom; or X⁵ is taken together withX^(5a) and the carbon atom to which they are attached and form apartially saturated or fully saturated 3- to 7-membered ring, or apartially saturated or fully saturated 4- to 8-membered ring having 1 to4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen; or X⁵ is taken together with X^(5a) and thecarbon atom to which they are attached and form a bicyclic ring systemconsisting of a partially saturated or fully saturated 5- or 6-memberedring, optionally having 1 or 2 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; Z¹ isa bond, O or N—X², provided that when a and b are both 0 then Z¹ is notN—X² or O; R⁷ and R⁸ are independently hydrogen or optionallysubstituted (C₁-C₆)alkyl; where the optionally substituted (C₁-C₆)alkylin the definition of R⁷ and R⁸ is optionally independently substitutedwith A¹, —C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1to 3 hydroxy, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or R⁷and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—; where L isC(X²)(X²), S(O)_(m) or N(X²); A¹ for each occurrence is independently(C₅-C₇)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen; A¹ for each occurrenceis independently optionally substituted, in one or optionally both ringsif A¹ is a bicyclic ring system, with up to three substituents, eachsubstituent independently selected from the group consisting of F, Cl,Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶, —C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², —NX⁶SO₂X¹²,—NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl, thiazolyl andtetrazolyl, provided that if A¹ is optionally substituted withmethylenedioxy then it can only be substituted with one methylenedioxy;where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² is hydrogen,(C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, X¹² is optionally substituted with one tothree substituents independently selected from the group consisting ofCl, F, CH₃, OCH₃, OCF₃ and CF₃ ⁻; or X¹¹ and X¹² are taken together toform —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²), O, S(O)_(m) orN(X²); r for each occurrence is independently 1, 2 or 3; X² for eachoccurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally substitutedwith —S(O)_(m)(C₁-C₆)alkyl, —C(O)X³, 1 to 5 halogens or 1-3 OX³; X³ foreach occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ isindependently hydrogen, optionally substituted (C₁-C₆)alkyl,(C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl,(C₃-C₇)-halogenatedcycloalkyl, where optionally substituted (C₁-C₆)alkyland optionally substituted (C₃-C₇)cycloalkyl in the definition of X⁶ isoptionally independently substituted by 1 or 2 (C₁-C₄)alkyl ester, or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷; X⁷ is hydrogen or (C₁-C₆)alkyl optionally substitutedwith hydroxyl; and m for each occurrence is independently 0, 1 or 2;with the proviso that: X⁶ and X¹² cannot be hydrogen when it is attachedto C(O) or SO₂ in the form C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²; and when R⁶is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 15. A method accordingto claim 1 wherein the condition associated with insulin resistance istype I diabetes, type II diabetes, hyperglycemia, impaired glucosetolerance or an insulin resistant syndrome or state.
 16. A methodaccording to claim 1 wherein the condition associated with insulinresistance is associated with obesity or old age.
 17. A method oftreating insulin resistance in a mammal which comprises administering toa mammal in need thereof an effective amount of a growth hormonereleasing peptide or a growh hormone releasing peptide mimetic or apharmaceutically acceptable salt thereof.
 18. A process for thepreparation of the compound of formula k,

which comprises reacting the compound of formula g,

with the compound of formula j,

where Prt is an amine protecting group, in the presence of an organicbase, a peptide coupling reagent, and a reaction inert solvent at atemperature between about −78° C. to about −20° C. to yield the compoundof formula k.
 19. A process according to claim 18 where the peptidecoupling reagent is 1-propane phosphonic acid cyclic anhydride and thecompound of formula g has the R-configuration, the compound of formula jhas the R-configuration and the compound of formula k has the3a-(R),1-(R) configuration.
 20. A process for the preparation of thecompound of formula Z,

which comprises reacting the compound of formula g,

with the compound of formula j,

in the presence of an organic base, a peptide coupling reagent, and areaction inert solvent at a temperature between about −78° C. to about−20° C. to yield the compound of formula k,

deprotecting the compound of formula k to yield the compound of formulaI,

reacting the compound of formula I with L-tartaric acid in an alcoholicsolvent to yield the compound of formula Z.
 21. A process according toclaim 20 where the peptide coupling reagent is 1-propane phosphonic acidcyclic anhydride and the compound of formula g has the R-configuration,the compound of formula j has the R-configuration and each of thecompounds of formula k, l and Z has the 3a-(R),1-(R) configuration. 22.A process for the preparation of the compound of formula g,

which comprises reacting the compound of formula f,

with a base in an inert solvent at a temperature of about −50 to −10° C.wherein the chirality of the benzyl group is maintained, to yield thecompound of formula g.
 23. A process for the preparation of the conpoundof formula c,

which comprises reacting the compound of formula b,

where Prt is an amine protecting group, with an inorganic or organicbase and benzyl bromide in a reaction inert solvent to yield thecompound of formula c.
 24. A process for the prepartation of thecompound of formula f,

which comprises reacting the compound of formula e,

with L-tartaric acid in a reaction inert organic solvent.
 25. TheR,S-enantiomeric mixture, the R-enantiomer or the S-enantiomer of thecompound of formula

where Prt is hydrogen or an amine protecting group.
 26. A method oftreating sleep disorders in a mammal suffering from sleep disorderscomprising administering to said mammal an effective amount of acompound of formula I

or the stereoisomeric mixtures, diastereomerically enriched,diastereomerically pure, anantiomerically enriched or enantiomericallypure isomers, or the pharmaceutically acceptable salts and prodrugsthereof, wherein e is 0 or 1; n and w are each independently 0, 1 or 2;provided that w and n cannot both be 0 at the same time; Y is oxygen orsulfur; R₁ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂_(q)N(X⁶)C(O)(CH₂)_(t)—A₁, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)—A¹,-(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂ _(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(Q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂OC(O)N(X⁶(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—¹, —(CH₂₎_(Q)N(X⁶)C(O)OX₆, —(CH₂)_(Q)N(X₆)SO₂N(X⁶(X⁶), —(CH₂S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(M)(CH₂ _(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y₁—(CH₂)_(t)—A₁ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-teterazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)NX⁶-, —CH═CH—,—C≡C—, —N(X⁶(C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—, q is 0,1, 2, 3, or 4; t is 0, 1, 2, or 3; said (CH₂)_(q) group and (CH₂)_(t)group may each be optionally substituted with hydrxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CH₂(C₁-C₄)alkyl ester ,1H-tetrazol-5-yl, 1, 2 or 3 fluoro, ir 1 or 2 (C₁-C₄)alkyl; R₂ ishydrogen, (C₁-C₈)alkyl, (C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹or A¹; where the alkyl groups are the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X^(6)(X) ⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl,—C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen; R³is A¹,(C₁-C₁₀)alkyl, -(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,-(C₁-C₅)alkyl-X-¹-(C₁-C₅)alkyl, -(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4, or 5 halogens, or 1, 2, or3 OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloaklyl, or R⁴ is taken to is taken together with R³ and thecarbon atom to which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇) cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated or orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X₅ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X_(5a)is consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX² , (C₃-C₇)cycloalkyl, —N(X²(X²) and —C(O)N(X²)(X²); or the carbon bearing X⁵or X^(5a) forms one or two alkylene bridges with the nitrogen atomsbearing R⁷ and R⁸ wherein each alkylene bridge contains 1 or 5 carbonatoms, provided that when one alkylene bridge is formed then X⁵ orX^(5a) but not both may be on the carbon atom and R⁷ or R⁸ but not bothmay be on the nitrogen atom and further provided that when two alkylenebridges are formed then X⁵ and X^(5a) cannot be on the carbon atom andR⁷ cannot be on the nitrogen atom; or X⁵ is taken together with X^(5a)and the carbon atom to which they are attached and form a partiallysaturated or fully saturated 3- to 7-membered ring, or partiallysaturated or fully saturated 4- to 8-membered ring having 1to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen; or X⁵ is taken together with X^(5a) and the carbonatom to which they are attached and form a bicyclic ring systemconsisting of a partially saturated or fully saturated 5- or 6-memberedring, optionally having 1 or 2 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; Z¹ isa bond, O or N-X², provided that when a and b are both 0 then Z¹ is notN—X² or O; R⁷ and R⁸ can independently hydrogen or optionallysubstituted (C₁-C_(6)alkyl;) where the optionally substituted(C₁-C₆)alkyl in the definition of R⁷ and R⁸ is optionally independentlysubstituted with A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5halogens, 1 to 3 hydroxy, 1 to 3 —O—C(O)(C₁-C₁₀) alkyl or 1 to 3(C₁-C₆)alkoxy; or R⁷ and R⁸ can be taken together to form—(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²(X²), S(O)_(m)or N(X²); A¹foreach occurrence is independently (C₅-C₇)cycloalkenyl, phenyl or apartially saturated, fully saturated or fully unsaturated 4- to8-membered ring optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, abicyclic ring system consisting of a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 or 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysatuarated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurance is independently optionally substituted,in one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisiting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, OCH₃,—OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, pheny, phenyol, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶)C(O)(X⁶),—S)₂N(X⁶)(X⁶), —N(X⁶)SO₂-phenyl —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹²,—NX⁶SO₂X¹², —NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl,thiazolyl and tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted with onemethylenedioxy; where X¹¹ is hydrogen or optionally substituted(C₁-C₆)alkyl; the optionally independently substituted with phenyl,phenoxy, (C₁-C₆) alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens,1 to 3 hydroxy, 1 to 3 (C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹²is hydrogen, (C₁-C₆)alkyl, pheny, thiazolyl, imidazolyl, furl orthienyl, provided that when X¹² is not hydrogen, X¹² is optionallysubstituted with one to three substitunets independtly selected from thegroup consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² aretaken together to form —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²),O, S(O)_(m) or N(X²); r for each occurance is independently 1, 2 or 3;X² for each occurance is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally subsitituted (C₃-C₇) cycloalkyl, where theoptionally substituted (C₁-C₆) alkyl and optioanlly sunstituted(C₃-C₇)cycloalkyl in the definition of X² are optioanlly independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³; X³ for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl, X⁶ is independently hydrpgen, optionallysubstituted (C₁-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenatedcycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optioanlly substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is independently subsitituted by 1 or 2(C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester, or1H-tetazol-5-yl; or when there are two X⁶ groups on one atome and bothare independently (C₁-C₆) alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷; X⁷ is hydrogen or (C₁-C₆)alkyl optioanlly substitutedwith hydroxyl; and m for each occurrence is independently 0, 1 or 2;with the proviso that: X⁶ and X¹² cannot be hydorgen when it is attachedto C(O) or SO₂ in the form C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²; and when R⁶is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3.